Heterocyclic compounds and uses thereof

ABSTRACT

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

This application claims priority to U.S. Provisional Application No.62/347,539, filed Jun. 8, 2016, the entirety of which is incorporatedherein by reference.

BACKGROUND

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (e.g., PI3-kinases, PI4-kinases),diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is also akey factor in many other diseases in humans PI3K signaling is involvedin many disease states including allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique and conserved family of intracellularlipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. The PI3K family comprises 15kinases with distinct substrate specificities, expression patterns, andmodes of regulation. The class I PI3Ks (p110α, p110β, p110δ, and p110γ)are typically activated by tyrosine kinases or G-protein coupledreceptors to generate PIP3, which engages downstream effectors such asthose in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rhofamily GTPases. The class II and III PI3Ks play a key role inintracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.The PI3Ks are protein kinases that control cell growth (mTORC1) ormonitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).

The delta (δ) isoform of class I PI3K has been implicated, inparticular, in a number of diseases and biological processes. PI3K-δ isexpressed primarily in hematopoietic cells including leukocytes such asT-cells, dendritic cells, neutrophils, mast cells, B-cells, andmacrophages. PI3K-δ is integrally involved in mammalian immune systemfunctions such as T-cell function, B-cell activation, mast cellactivation, dendritic cell function, and neutrophil activity. Due to itsintegral role in immune system function, PI3K-δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, and auto-immune diseases such aslupus, asthma, emphysema and other respiratory diseases. Other class IPI3K involved in immune system function includes PI3K-γ, which plays arole in leukocyte signaling and has been implicated in inflammation,rheumatoid arthritis, and autoimmune diseases such as lupus. Forexample, PI3K-γ and PI3K-δ are highly expressed in leukocytes and havebeen associated with adaptive and innate immunity; thus, these PI3Kisoforms can be important mediators in inflammatory disorders andhematologic malignancies.

The gamma (γ) isoform of class I PI3K consists of a catalytic subunitp110γ, which is associated with a p101 regulatory subunit. PI3K-γ isregulated by G protein-coupled receptors (GPCRs) via association withthe β/γ subunits of heterotrimeric G proteins. PI3K-γ is expressedprimarily in hematopoietic cells and cardiomyocytes and is involved ininflammation and mast cell function. Inhibitors of PI3K-γ are useful fortreating a variety of inflammatory diseases, allergies, andcardiovascular diseases, among others.

Unlike PI3K-δ, the beta (β) isoform of class I PI3K appears to beubiquitously expressed. PI3K-β has been implicated primarily in varioustypes of cancer including PTEN-negative cancer (Edgar et al. CancerResearch (2010) 70(3):1164-1172), and HER2-overexpressing cancer such asbreast cancer and ovarian cancer.

SUMMARY

Described herein are compounds capable of selectively inhibiting one ormore isoform(s) of class I PI3K without substantially affecting theactivity of the remaining isoforms of the same class. For example, insome embodiments, non-limiting examples of inhibitors capable ofselectively inhibiting PI3K-δ and/or PI3K-γ, but without substantiallyaffecting the activity of PI3K-α and/or PI3K-β are disclosed. In oneembodiment, the inhibitors provided herein can be effective inameliorating disease conditions associated with PI3K-δ and/or PI3K-γactivity. In one embodiment, the compounds are capable of selectivelyinhibiting PI3K-γ over PI3K-δ.

Provided herein are compounds of Formula I″:

or a pharmaceutically acceptable form thereof, wherein A, B, L, W_(d),R, R^(1b), R^(2b), R^(3b), R^(4b), R^(5b), R^(1c), and R^(2c) are asdescribed herein.

In one embodiment, the compound provided herein is predominately in an(S)-stereochemical configuration. In one embodiment, the compoundprovided herein is the S enantiomer having an enantiomeric excessselected from greater than about 25%, greater than about 55%, greaterthan about 80%, greater than about 90%, and greater than about 95%. Inone embodiment, the compound is present in a pharmaceutical compositioncomprising the compound, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable excipients.

In certain embodiments, a compound disclosed herein selectivelymodulates PI3K gamma isoform. In certain embodiments, the compoundselectively inhibits the gamma isoform over the alpha or beta isoform.By way of non-limiting example, the ratio of selectivity can be greaterthan a factor of about 10, greater than a factor of about 50, greaterthan a factor of about 100, greater than a factor of about 200, greaterthan a factor of about 400, greater than a factor of about 600, greaterthan a factor of about 800, greater than a factor of about 1000, greaterthan a factor of about 1500, greater than a factor of about 2000,greater than a factor of about 5000, greater than a factor of about10,000, or greater than a factor of about 20,000, where selectivity canbe measured by ratio of IC₅₀ values, among other means. In oneembodiment, the selectivity of PI3K gamma isoform over PI3K alpha orbeta isoform is measured by the ratio of the IC₅₀ value against PI3Kalpha or beta isoform to the IC₅₀ value against PI3K gamma isoform. Incertain embodiments, the PI3K gamma isoform IC₅₀ activity of a compounddisclosed herein can be less than about 1000 nM, less than about 100 nM,less than about 10 nM, or less than about 1 nM.

In certain embodiments, a compound disclosed herein selectivelymodulates PI3K gamma isoform over the delta isoform. By way ofnon-limiting example, the ratio of selectivity can be greater than afactor of about 10, greater than a factor of about 50, greater than afactor of about 100, greater than a factor of about 200, greater than afactor of about 400, greater than a factor of about 600, greater than afactor of about 800, greater than a factor of about 1000, greater than afactor of about 1500, greater than a factor of about 2000, greater thana factor of about 5000, greater than a factor of about 10,000, orgreater than a factor of about 20,000, where selectivity can be measuredby ratio of IC₅₀ values, among other means. In one embodiment, theselectivity of PI3K gamma isoform over PI3K delta isoform is measured bythe ratio of the IC₅₀ value against PI3K delta isoform to the IC₅₀ valueagainst PI3K gamma isoform.

In certain embodiments, a compound as disclosed herein selectivelymodulates PI3K delta isoform. In certain embodiments, the compoundselectively inhibits the delta isoform over the alpha or beta isoform.By way of non-limiting example, the ratio of selectivity can be greaterthan a factor of about 10, greater than a factor of about 50, greaterthan a factor of about 100, greater than a factor of about 200, greaterthan a factor of about 400, greater than a factor of about 600, greaterthan a factor of about 800, greater than a factor of about 1000, greaterthan a factor of about 1500, greater than a factor of about 2000,greater than a factor of about 5000, greater than a factor of about10,000, or greater than a factor of about 20,000, where selectivity canbe measured by ratio of IC₅₀ values, among other means. In oneembodiment, the selectivity of PI3K delta isoform over PI3K alpha orbeta isoform is measured by the ratio of the IC₅₀ value against PI3Kalpha or beta isoform to the IC₅₀ value against PI3K delta isoform. Incertain embodiments, the PI3K delta isoform IC₅₀ activity of a compounddisclosed herein can be less than about 1000 nM, less than about 100 nM,less than about 10 nM, or less than about 1 nM.

In certain embodiments, provided herein is a composition (e.g., apharmaceutical composition) comprising a compound described herein and apharmaceutically acceptable excipient. In some embodiments, providedherein is a method of inhibiting a PI3 kinase, comprising contacting thePI3 kinase with an effective amount of a compound or a pharmaceuticalcomposition described herein. In certain embodiments, a method isprovided for inhibiting a PI3 kinase wherein said PI3 kinase is presentin a cell. The inhibition can take place in a subject suffering from adisorder selected from cancer, bone disorder, inflammatory disease,immune disease, nervous system disease (e.g., a neuropsychiatricdisorder), metabolic disease, respiratory disease, thrombosis, andcardiac disease, among others. In certain embodiments, a secondtherapeutic agent is administered to the subject.

In certain embodiments, a method is provided for selectively inhibitinga PI3 kinase gamma isoform over PI3 kinase alpha or beta isoform whereinthe inhibition takes place in a cell. Non-limiting examples of themethods disclosed herein can comprise contacting PI3 kinase gammaisoform with an effective amount of a compound or a pharmaceuticalcomposition disclosed herein. In an embodiment, such contact can occurin a cell.

In certain embodiments, a method is provided for selectively inhibitinga PI3 kinase gamma isoform over PI3 kinase alpha or beta isoform whereinthe inhibition takes place in a subject suffering from a disorderselected from cancer, bone disorder, inflammatory disease, immunedisease, nervous system disease (e.g., a neuropsychiatric disorder),metabolic disease, respiratory disease, thrombosis, and cardiac disease,said method comprising administering an effective amount of a compoundor a pharmaceutical composition provided herein to said subject. Incertain embodiments, provided herein is a method of treating a subjectsuffering from a disorder associated with PI3 kinase, said methodcomprising selectively modulating the PI3 kinase gamma isoform over PI3kinase alpha or beta isoform by administering an amount of a compound ora pharmaceutical composition provided herein to said subject, whereinsaid amount is sufficient for selective modulation of PI3 kinase gammaisoform over PI3 kinase alpha or beta isoform.

In certain embodiments, a method is provided for selectively inhibitinga PI3 kinase delta isoform over PI3 kinase alpha or beta isoform whereinthe inhibition takes place in a cell. Non-limiting examples of themethods disclosed herein can comprise contacting PI3 kinase deltaisoform with an effective amount of a compound or a pharmaceuticalcomposition disclosed herein. In an embodiment, such contact can occurin a cell.

In certain embodiments, a method is provided for selectively inhibitinga PI3 kinase delta isoform over PI3 kinase alpha or beta isoform whereinthe inhibition takes place in a subject suffering from a disorderselected from cancer, bone disorder, inflammatory disease, immunedisease, nervous system disease (e.g., a neuropsychiatric disorder),metabolic disease, respiratory disease, thrombosis, and cardiac disease,said method comprising administering an effective amount of a compoundor a pharmaceutical composition provided herein to said subject. Incertain embodiments, provided herein is a method of treating a subjectsuffering from a disorder associated with PI3 kinase, said methodcomprising selectively modulating the PI3 kinase delta isoform over PI3kinase alpha or beta isoform by administering an amount of a compound ora pharmaceutical composition provided herein to said subject, whereinsaid amount is sufficient for selective modulation of PI3 kinase deltaisoform over PI3 kinase alpha or beta isoform.

In certain embodiments, a method is provided for selectively inhibitinga PI3 kinase gamma isoform over PI3 kinase delta isoform wherein theinhibition takes place in a cell. Non-limiting examples of the methodsdisclosed herein can comprise contacting PI3 kinase gamma isoform withan effective amount of a compound or a pharmaceutical compositiondisclosed herein. In an embodiment, such contact can occur in a cell.

In certain embodiments, a method is provided for selectively inhibitinga PI3 kinase gamma isoform over PI3 kinase delta isoform wherein theinhibition takes place in a subject suffering from a disorder selectedfrom cancer, bone disorder, inflammatory disease, immune disease,nervous system disease (e.g., a neuropsychiatric disorder), metabolicdisease, respiratory disease, thrombosis, and cardiac disease, saidmethod comprising administering an effective amount of a compound or apharmaceutical composition provided herein to said subject. In certainembodiments, provided herein is a method of treating a subject sufferingfrom a disorder associated with PI3 kinase, said method comprisingselectively modulating the PI3 kinase gamma isoform over PI3 kinasedelta isoform by administering an amount of a compound or apharmaceutical composition provided herein to said subject, wherein saidamount is sufficient for selective modulation of PI3 kinase gammaisoform over PI3 kinase delta isoform.

In certain embodiments, provided herein is a method of inhibiting a PI3kinase in a subject suffering from an inflammatory disease, an immunedisease, or a respiratory disease, comprising administering to thesubject an effective amount of a compound provided herein (e.g., acompound of Formula I′, Formula II′, Formula I, or Formula II). In oneembodiment, the subject is a mammal. In one embodiment, the mammal is ahuman. In one embodiment, the subject is a human.

In some embodiments, the disorder suffered by the subject is a cancer.In one embodiment, the cancer is a hematological cancer. In oneembodiment, the cancer is acute myeloid leukemia (AML), chronic myeloidleukemia (CML), myelodysplastic syndrome (MDS), myeloproliferativedisorders, mast cell cancer, Hodgkin disease, non-Hodgkin lymphomas,diffuse large B-cell lymphoma, human lymphotrophic virus type 1 (HTLV-1)leukemia/lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, acutelymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia, B-cellacute lymphoblastic leukemia, chronic lymphocytic leukemia, or multiplemyeloma (MM). In one embodiment, the cancer is leukemia or lymphoma. Inone embodiment, the leukemia is B-cell acute lymphoblastic leukemia(B-ALL), acute myeloid leukemia (AML), acute lymphocytic leukemia,chronic myeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiplemyeloma (MM), myelodysplastic syndrome (MDS), or mast cell cancer. Inone embodiment, the lymphoma is diffuse large B-cell lymphoma, B-cellimmunoblastic lymphoma, small non-cleaved cell lymphoma, humanlymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-celllymphoma, Hodgkin disease, or non-Hodgkin lymphomas.

In one embodiment, the cancer is a solid tumor. In one embodiment, thecancer is lung cancer, e.g., non-small cell lung cancer, small cell lungcancer; melanoma; prostate cancer; glioblastoma; endometrial cancer;pancreatic cancer; renal cell carcinoma; colorectal cancer; breastcancer; thyroid cancer; or ovarian cancer. In one embodiment, the solidtumor is prostate cancer, breast cancer, or glioblastomas.

In some embodiments, the disorder suffered by the subject is aninflammatory disease or an immune disease. In one embodiment, theinflammatory disease or the immune disease is asthma, emphysema,allergy, dermatitis, rheumatoid arthritis, psoriasis, lupuserythematosus, graft versus host disease, inflammatory bowel disease,eczema, scleroderma, Crohn's disease, or multiple sclerosis. In oneembodiment, the disorder is rheumatoid arthritis. In one embodiment, thedisorder is rheumatoid arthritis, and the amount of the compound iseffective to ameliorate one or more symptoms associated with rheumatoidarthritis, wherein the symptom associated with rheumatoid arthritis isindependently a reduction in the swelling of the joints, a reduction inserum anti collagen levels, a reduction in bone resorption, a reductionin cartilage damage, a reduction in pannus, or a reduction ininflammation.

In some embodiments, the disorder suffered by the subject is arespiratory disease. In one embodiment, the respiratory disease isasthma, chronic obstructive pulmonary disease (COPD), chronicbronchitis, emphysema, or bronchiectasis. In one embodiment, thedisorder is asthma.

In one embodiment, the methods provided herein further compriseadministration of one or more therapeutic agents selected fromchemotherapeutic agents, cytotoxic agents, and radiation. In oneembodiment, the compound is administered in combination with an mTORinhibitor. In one embodiment, the compound is administered incombination with one or more of: an agent that inhibits IgE productionor activity, 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoicacid, an mTOR inhibitor, rapamycin, a TORC1 inhibitor, a TORC2inhibitor, an anti-IgE antibody, prednisone, corticosteroid, aleukotriene inhibitor, XOLAIR, ADVAIR, SINGULAIR, or SPIRIVA. In oneembodiment, the compound is administered in combination with one or moreof: a mitotic inhibitor, an alkylating agent, an anti-metabolite, anintercalating antibiotic, a growth factor inhibitor, a cell cycleinhibitor, an enzyme, a topoisomerase inhibitor, an anti-hormone, anangiogenesis inhibitor, an anti-androgen, or an anti-receptor kinaseantibody. In one embodiment, the compound is administered in combinationwith one or more of: Imatinib Mesylate, bortezomib, bicalutamide,gefitinib, ADRIAMYCIN, alkylating agents, alkyl sulfonates,ethylenimines, altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide,trimethylolomelamine, nitrogen mustards, chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosureas,antibiotics, anti-metabolites, denopterin, methotrexate, pteropterin,trimetrexate, 5-fluorouracil (5-FU), fludarabine, 6-mercaptopurine,thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens, anti-adrenals, folic acid replenisher,arabinoside, cyclophosphamide, thiotepa, taxanes, anti-hormonal agents,anti-estrogens, tamoxifen, raloxifene, aromatase inhibiting4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone,toremifene, anti-androgens, chlorambucil, gemcitabine, 6-thioguanine;mercaptopurine; cisplatin, carboplatin, vincristine; vinorelbine,vinblastin, ifosfamide, mitomycin C, daunorubicin, doxorubicin,mitoxantrone, HERCEPTIN, AVASTIN, ERBITUX, RITUXAN, TAXOL, ARIMIDEX,TAXOTERE, or an anti-receptor tyrosine kinase antibody selected fromcetuximab, panitumumab, trastuzumab, anti CD20 antibody, rituximab,tositumomab, alemtuzumab, bevacizumab, and gemtuzumab. In oneembodiment, the compound is administered in combination with one or moreof: bortezomib, ADRIAMYCIN, alkylating agents, anti-metabolites,denopterin, pteropterin, trimetrexate, a nitrogen mustard, chlorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard,methotrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine,ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens,cyclophosphamide, taxanes, anti-hormonal agents, gemcitabine; cisplatin,carboplatin, vincristine, vinorelbine, vinblastin, ifosfamide, mitomycinC, daunorubicin, doxorubicin, mitoxantrone, HERCEPTIN, AVASTIN, ERBITUX,RITUXAN, TAXOL, ARIMIDEX, or TAXOTERE. In one embodiment, the compoundis administered in combination with one or more of: non-steroidalanti-inflammatory drugs (NSAIDs), corticosteroids, prednisone,chloroquine, hydroxychloroquine, azathioprine, cyclophosphamide,methotrexate, cyclosporine, anti-CD20 antibodies, ENBREL, REMICADE,HUMIRA, AVONEX, or REBIF.

In one embodiment, provided herein is a method of inhibiting a PI3kinase in a subject suffering from a cancer, comprising administering tothe subject an effective amount of a compound provided herein (e.g., acompound of Formula I′). In one embodiment, the cancer is selected fromacute myeloid leukemia (AML), chronic myeloid leukemia (CML),myelodysplastic syndrome (MDS), myeloproliferative disorders, mast cellcancer, Hodgkin disease, non-Hodgkin lymphomas, diffuse large B-celllymphoma, human lymphotrophic virus-type 1 (HTLV-1) leukemia/lymphoma,AIDS-related lymphoma, adult T-cell lymphoma, acute lymphocytic leukemia(ALL), B-cell acute lymphoblastic leukemia, T-cell acute lymphoblasticleukemia, chronic lymphocytic leukemia, or multiple myeloma (MM). In oneembodiment, the cancer is leukemia or lymphoma. In one embodiment, theleukemia is selected from B-cell acute lymphoblastic leukemia (B-ALL),acute lymphocytic leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiplemyeloma (MM), myelodysplastic syndrome (MDS), or mast cell cancer. Inone embodiment, the lymphoma is selected from diffuse large B-celllymphoma, B-cell immunoblastic lymphoma, small non-cleaved celllymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma,AIDS-related lymphoma, adult T-cell lymphoma, Hodgkin disease, ornon-Hodgkin lymphomas. In one embodiment, the compound is administeredin combination with one or more therapeutic agents provided herein.

In one embodiment, provided herein is a method of inhibiting a PI3kinase in a subject suffering from an inflammatory disease or an immunedisease, comprising administering to the subject an effective amount ofa compound provided herein (e.g., a compound of Formula I′). In oneembodiment, the inflammatory disease or immune disease is asthma,emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupuserythematosus, graft versus host disease, inflammatory bowel disease,eczema, scleroderma, Crohn's disease, or multiple sclerosis. In oneembodiment, the inflammatory disease or immune disease is rheumatoidarthritis. In one embodiment, the compound is administered incombination with one or more therapeutic agents provided herein.

In one embodiment, provided herein is a method of inhibiting a PI3kinase in a subject suffering from a respiratory disease, comprisingadministering to the subject an effective amount of a compound providedherein (e.g., a compound of Formula I′). In one embodiment, therespiratory disease is asthma, chronic obstructive pulmonary disease(COPD), chronic bronchitis, emphysema, or bronchiectasis. In oneembodiment, the respiratory disease is asthma In one embodiment, thecompound is administered in combination with one or more therapeuticagents provided herein.

In certain embodiments, provided herein is a method of inhibiting PI3K-γin a subject, comprising administering to the subject an effectiveamount of a compound provided herein (e.g., a compound of Formula I′).

In certain embodiments, provided herein is a method of inhibiting PI3K-δin a subject, comprising administering to the subject an effectiveamount of a compound provided herein (e.g., a compound of Formula I′).

In certain embodiments, provided herein is a method of making a compounddescribed herein.

In certain embodiments, provided herein is a reaction mixture comprisinga compound described herein.

In certain embodiments, provided herein is a kit comprising a compounddescribed herein.

In some embodiments, a method is provided for treating a disease ordisorder described herein, the method comprising administering atherapeutically effective amount of a compound or a pharmaceuticalcomposition described herein to a subject.

In some embodiments, a method is provided for treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or a pharmaceuticalcomposition described herein to a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of adisease or disorder described herein in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of a PI3Kmediated disorder in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a disease or disorder described hereinin a subject.

In some embodiments, provided herein is use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a PI3K mediated disorder in a subject.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

DETAILED DESCRIPTION

In one embodiment, provided are heterocyclyl compounds, andpharmaceutically acceptable forms thereof, including, but not limitedto, salts, hydrates, solvates, isomers, prodrugs, and isotopicallylabeled derivatives thereof.

In another embodiment, provided are methods of treating and/or managingvarious diseases and disorders, which comprises administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof. Examples of diseases and disorders are described herein.

In another embodiment, provided are methods of preventing variousdiseases and disorders, which comprises administering to a patient inneed of such prevention a prophylactically effective amount of acompound provided herein, or a pharmaceutically acceptable form (e.g.,salts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. Examples of diseases and disorders are describedherein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, is administered incombination with another drug (“second active agent”) or treatment.Second active agents include small molecules and large molecules (e.g.,proteins and antibodies), examples of which are provided herein, as wellas stem cells. Other methods or therapies that can be used incombination with the administration of compounds provided hereininclude, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, and optionally one or more second active agents.

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, or 0.05% of a given value or range.

As used herein, “agent” or “biologically active agent” or “second activeagent” refers to a biological, pharmaceutical, or chemical compound orother moiety. Non-limiting examples include simple or complex organic orinorganic molecules, a peptide, a protein, an oligonucleotide, anantibody, an antibody derivative, an antibody fragment, a vitamin, avitamin derivative, a carbohydrate, a toxin, or a chemotherapeuticcompound, and metabolites thereof. Various compounds can be synthesized,for example, small molecules and oligomers (e.g., oligopeptides andoligonucleotides), and synthetic organic compounds based on various corestructures. In addition, various natural sources can provide compoundsfor screening, such as plant or animal extracts, and the like. A skilledartisan can readily recognize that there is no limit as to thestructural nature of the agents of this disclosure.

The term “agonist” as used herein refers to a compound or agent havingthe ability to initiate or enhance a biological function of a targetprotein or polypeptide, such as increasing the activity or expression ofthe target protein or polypeptide. Accordingly, the term “agonist” isdefined in the context of the biological role of the target protein orpolypeptide. While some agonists herein specifically interact with(e.g., bind to) the target, compounds and/or agents that initiate orenhance a biological activity of the target protein or polypeptide byinteracting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound or agent having the ability to inhibit abiological function of a target protein or polypeptide, such as byinhibiting the activity or expression of the target protein orpolypeptide. Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein orpolypeptide. While some antagonists herein specifically interact with(e.g., bind to) the target, compounds that inhibit a biological activityof the target protein or polypeptide by interacting with other membersof the signal transduction pathway of which the target protein orpolypeptide are also specifically included within this definition.Non-limiting examples of biological activity inhibited by an antagonistinclude those associated with the development, growth, or spread of atumor, or an undesired immune response as manifested in autoimmunedisease.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, or buccal administration, orinhalation, or in the form of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to subject so that both agents and/or theirmetabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or pharmaceutical composition describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment, as illustrated below. Thetherapeutically effective amount can vary depending upon the intendedapplication (in vitro or in vivo), or the subject and disease conditionbeing treated, e.g., the weight and age of the subject, the severity ofthe disease condition, the manner of administration and the like, whichcan readily be determined by one of ordinary skill in the art. The termalso applies to a dose that will induce a particular response in targetcells, e.g., reduction of platelet adhesion and/or cell migration. Thespecific dose will vary depending on, for example, the particularcompounds chosen, the dosing regimen to be followed, whether it isadministered in combination with other agents, timing of administration,the tissue to which it is administered, and the physical delivery systemin which it is carried.

As used herein, the terms “treatment”, “treating”, “palliating” and“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including, but notlimited to, therapeutic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient can still be afflicted withthe underlying disorder.

As used herein, the terms “prevention” and “preventing” are used hereinto refer to an approach for obtaining beneficial or desired resultsincluding, but not limited, to prophylactic benefit. For prophylacticbenefit, the pharmaceutical compositions can be administered to apatient at risk of developing a particular disease, or to a patientreporting one or more of the physiological symptoms of a disease, eventhough a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A “modulator” of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator can augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or indirect interaction with the target. Forexample, a compound that selectively inhibits one isoform of PI3K overanother isoform of PI3K has an activity of at least greater than about1× against a first isoform relative to the compound's activity againstthe second isoform (e.g., at least about 2×, 3×, 5×, 10×, 20×, 50×,100×, 200×, 500×, or 1000×). In certain embodiments, these terms referto (1) a compound of described herein that selectively inhibits thegamma isoform over the alpha, beta, or delta isoform; or (2) a compounddescribed herein that selectively inhibits the delta isoform over thealpha or beta isoform. By way of non-limiting example, the ratio ofselectivity can be greater than a factor of about 1, greater than afactor of about 2, greater than a factor of about 3, greater than afactor of about 5, greater than a factor of about 10, greater than afactor of about 50, greater than a factor of about 100, greater than afactor of about 200, greater than a factor of about 400, greater than afactor of about 600, greater than a factor of about 800, greater than afactor of about 1000, greater than a factor of about 1500, greater thana factor of about 2000, greater than a factor of about 5000, greaterthan a factor of about 10,000, or greater than a factor of about 20,000,where selectivity can be measured by IC₅₀ e.g., in vitro or in vivoassays such as those described in Examples 222, 224, 225, 226, 247, 248,etc. In certain embodiments, the IC₅₀ can be measured by in vitro or invivo assays such as those described in Examples 247 and 248. In certainembodiments, the PI3K gamma isoform IC₅₀ activity of a compound ofprovided herein can be less than about 1000 nM, less than about 500 nM,less than about 400 nM, less than about 300 nM, less than about 200 nM,less than about 100 nM, less than about 75 nM, less than about 50 nM,less than about 25 nM, less than about 20 nM, less than about 15 nM,less than about 10 nM, less than about 5 nM, or less than about 1 nM. Incertain embodiments, the PI3K delta isoform IC₅₀ activity of a compoundprovided herein can be less than about 1000 nM, less than about 500 nM,less than about 400 nM, less than about 300 nM, less than about 200 nM,less than about 100 nM, less than about 75 nM, less than about 50 nM,less than about 25 nM, less than about 20 nM, less than about 15 nM,less than about 10 nM, less than about 5 nM, or less than about 1 nM.

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such as,but not limited to, alpha-particle emitting radionuclides (e.g.,actinium and thorium radionuclides), low linear energy transfer (LET)radiation emitters (e.g., beta emitters), conversion electron emitters(e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation,including without limitation x-rays, gamma rays, and neutrons.

“Subject” to which administration is contemplated includes, but is notlimited to, humans (e g., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, quail, and/or turkeys.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assayconducted outside of a subject. In vitro assays encompass cell-basedassays in which cells, alive or dead, are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

As used herein, “pharmaceutically acceptable esters” include, but arenot limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkylesters of acidic groups, including, but not limited to, carboxylicacids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinicacids, and boronic acids.

As used herein, “pharmaceutically acceptable enol ethers” include, butare not limited to, derivatives of formula —C═C(OR) where R can beselected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula —C═C(OC(O)R) where R can be selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl.

As used herein, a “pharmaceutically acceptable form” of a disclosedcompound includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives of disclosed compounds. In one embodiment, a“pharmaceutically acceptable form” includes, but is not limited to,pharmaceutically acceptable salts, isomers, prodrugs and isotopicallylabeled derivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. In some embodiments, organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, andaryl sulfonate. Organic bases from which salts can be derived include,for example, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

In certain embodiments, the pharmaceutically acceptable form is asolvate (e.g., a hydrate). As used herein, the term “solvate” refers tocompounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or one toabout 2, about 3 or about 4, solvent or water molecules. It will beunderstood that the term “compound” as used herein encompasses thecompound and solvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. As used herein, the term “prodrug” refers to compounds that aretransformed in vivo to yield a disclosed compound or a pharmaceuticallyacceptable form of the compound. A prodrug can be inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis (e.g., hydrolysis in blood). Incertain cases, a prodrug has improved physical and/or deliveryproperties over the parent compound. Prodrugs are typically designed toenhance pharmaceutically and/or pharmacokinetically based propertiesassociated with the parent compound. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs isprovided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated in full byreference herein. Exemplary advantages of a prodrug can include, but arenot limited to, its physical properties, such as enhanced watersolubility for parenteral administration at physiological pH compared tothe parent compound, or it enhances absorption from the digestive tract,or it can enhance drug stability for long-term storage.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elsevier, New York, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂, and glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H ormethyl and Y⁵ is mono-N- or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” are different compounds that have the same molecularformula. “Atropisomers” are stereoisomers from hindered rotation aboutsingle bonds and can be resolved or isolated by methods known to thoseskilled in the art. For example, certain substituents with ortho or metasubstituted phenyl may form atropisomers, where they may be separatedand isolated.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. As used herein, the term “isomer” includes any andall geometric isomers and stereoisomers. For example, “isomers” includegeometric double bond cis- and trans-isomers, also termed E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and(l)-isomers, racemic mixtures thereof; and other mixtures thereof, asfalling within the scope of this disclosure.

In certain embodiments, the symbol

denotes a bond that can be a single or double as described herein.

In certain embodiments, provided herein are various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “F” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of the plane of thering are designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(±)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry can bespecified according to the Cahn-Ingold-Prelog R—S system. When acompound is an enantiomer, the stereochemistry at each chiral carbon canbe specified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and can thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat can be defined, in terms of absolute stereochemistry at eachasymmetric atom, as (R)— or (S)—. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically substantiallypure forms and intermediate mixtures. Optically active (R)- and(S)-isomers can be prepared, for example, using chiral synthons orchiral reagents, or resolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., an Senantiomer, and 10% of the other enantiomer, e.g., an R enantiomer.

ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about50%, about 75%, about 90%, about 95%, or about 99% of the S enantiomer.In other words, the compositions contain an enantiomeric excess of the Senantiomer over the R enantiomer. In other embodiments, somecompositions described herein contain an enantiomeric excess of at leastabout 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about50%, about 75%, about 90%, about 95%, or about 99% of the R enantiomer.In other words, the compositions contain an enantiomeric excess of the Renantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the amount of oneenantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than 1:1 byweight). For example, an enantiomerically enriched preparation of the Senantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the total weight ofthe preparation (e.g., total weight of S and R isomers). such as atleast about 75% by weight, further such as at least about 80% by weight.In some embodiments, the enrichment can be much greater than about 80%by weight, providing a “substantially enantiomerically enriched,”“substantially enantiomerically pure” or a “substantially non-racemic”preparation, which refers to preparations of compositions which have atleast about 85% by weight of one enantiomer relative to the total weightof the preparation, such as at least about 90% by weight, and furthersuch as at least about 95% by weight. In certain embodiments, thecompound provided herein is made up of at least about 90% by weight ofone enantiomer. In other embodiments, the compound is made up of atleast about 95%, about 98%, or about 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, insome embodiments, the compound mixture has an (S)-enantiomeric excess ofgreater than about 10%, greater than about 20%, greater than about 30%,greater than about 40%, greater than about 50%, greater than about 55%,greater than about 60%, greater than about 65%, greater than about 70%,greater than about 75%, greater than about 80%, greater than about 85%,greater than about 90%, greater than about 95%, greater than about 96%,greater than about 97%, greater than about 98%, or greater than about99%. In some embodiments, the compound mixture has an (S)-enantiomericexcess of about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, or about 99.5%, or more. In some embodiments, the compoundmixture has an (S)-enantiomeric excess of about 55% to about 99.5%,about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% toabout 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%,or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the compound mixture has an (R)-enantiomericexcess of greater than about 10%, greater than about 20%, greater thanabout 30%, greater than about 40%, greater than about 50%, greater thanabout 55%, greater than about 60%, greater than about 65%, greater thanabout 70%, greater than about 75%, greater than about 80%, greater thanabout 85%, greater than about 90%, greater than about 95%, greater thanabout 96%, greater than about 97%, greater than about 98%, or greaterthan about 99%. In some embodiments, the compound mixture has an(R)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments,the compound mixture has an (R)-enantiomeric excess of about 55% toabout 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%,about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% toabout 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities (i.e., (S)- or (R)-stereoisomers). In some embodiments, themixture of identical chemical entities (i.e., mixture of stereoisomers)is a racemic mixture of (S)- and (R)-isomers. In another embodiment, themixture of the identical chemical entities (i.e., mixture ofstereoisomers) contains predominately (9-isomer or predominately(R)-isomer. For example, in some embodiments, the (9-isomer in themixture of identical chemical entities (i.e., mixture of stereoisomers)is present at about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, about 99%, or about 99.5% by weight, or more, relative to the totalweight of the mixture of (S)- and (R)-isomers. In some embodiments, the(9-isomer in the mixture of identical chemical entities (i.e., mixtureof stereoisomers) is present at an (9-enantiomeric excess of about 10%to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%,about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% toabout 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%,about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the (R)-isomer in the mixture of identicalchemical entities (i.e., mixture of stereoisomers) is present at about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, orabout 99.5% by weight, or more, relative to the total weight of themixture of (S)- and (R)-isomers. In some embodiments, the (R)-isomers inthe mixture of identical chemical entities (i.e., mixture ofstereoisomers) is present at an (R)-enantiomeric excess of about 10% toabout 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%,about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% toabout 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%,or about 99% to about 99.5%, or more than about 99.5%.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example,Enantiomers, Racemates and Resolutions (Jacques, Ed., WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, NY,1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertable compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a doublebond, or a triple bond to a single bond, or vice versa).“Tautomerization” includes prototropic or proton-shift tautomerization,which is considered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order. The exactratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Where tautomerization is possible (e.g.,in solution), a chemical equilibrium of tautomers can be reached.Tautomerizations (i.e., the reaction providing a tautomeric pair) can becatalyzed by acid or base, or can occur without the action or presenceof an external agent. Exemplary tautomerization include, but are notlimited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; andenamine-(a different) enamine tautomerization. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. A specific example ofphenol-keto tautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement or enrichment of a hydrogen bydeuterium or tritium at one or more atoms in the molecule, or thereplacement or enrichment of a carbon by ¹³C or ¹⁴C at one or more atomsin the molecule, are within the scope of this disclosure. In oneembodiment, provided herein are isotopically labeled compounds havingone or more hydrogen atoms replaced by or enriched by deuterium. In oneembodiment, provided herein are isotopically labeled compounds havingone or more hydrogen atoms replaced by or enriched by tritium. In oneembodiment, provided herein are isotopically labeled compounds havingone or more carbon atoms replaced or enriched by ¹³C. In one embodiment,provided herein are isotopically labeled compounds having one or morecarbon atoms replaced or enriched by ¹⁴C.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur,fluorine, and chlorine, such as, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Certain isotopically-labeleddisclosed compounds (e.g., those labeled with ³H and/or ¹⁴C) are usefulin compound and/or substrate tissue distribution assays. Tritiated(i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can allow for ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) can afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements). Isotopically labeleddisclosed compounds can generally be prepared by substituting anisotopically labeled reagent for a non-isotopically labeled reagent. Insome embodiments, provided herein are compounds that can also containunnatural proportions of atomic isotopes at one or more of atoms thatconstitute such compounds. All isotopic variations of the compounds asdisclosed herein, whether radioactive or not, are encompassed within thescope of the present disclosure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions as disclosedherein is contemplated. Supplementary active ingredients can also beincorporated into the pharmaceutical compositions.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley& Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge UniversityPress, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having, in some embodiments, from one to ten carbon atoms(e.g., C₁-C₁₀ alkyl). Linear or straight alkyl refers to an alkyl withno branching, e.g., methyl, ethyl, n-propyl. Whenever it appears herein,a numerical range such as “1 to 10” refers to each integer in the givenrange; e.g., “1 to 10 carbon atoms” means that the alkyl group canconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, etc., up to and including 10 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated. In some embodiments, an alkyl is a C₁-C₆alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 6, 1to 4, or 1 to 3 carbon atoms. Representative saturated straight chainalkyls include, but are not limited to, -methyl, -ethyl, -n-propyl,-n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkylsinclude, but are not limited to, -isopropyl, -sec-butyl, -isobutyl,-tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkylis attached to the parent molecule by a single bond. Unless statedotherwise in the specification, an alkyl group is optionally substitutedby one or more of substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like. “Haloalkyl”refers to an alkyl group in which one or more of the hydrogen atoms havebeen replaced with a halogen independently selected from fluoro, chloro,bromo, and iodo.

“Alkyl-cycloalkyl” refers to an -(alkyl)cycloalkyl radical where alkyland cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkyl and cycloalkyl respectively. The“alkyl-cycloalkyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “alkenyl-cycloalkyl” and “alkynyl-cycloalkyl”mirror the above description of “alkyl-cycloalkyl” wherein the term“alkyl” is replaced with “alkenyl” or “alkynyl” respectively, and“alkenyl” or “alkynyl” are as described herein.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively. The “alkylaryl” is bonded to the parent molecularstructure through the alkyl group. The terms “-(alkenyl)aryl” and“-(alkynyl)aryl” mirror the above description of “-(alkyl)aryl” whereinthe term “alkyl” is replaced with “alkenyl” or “alkynyl” respectively,and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-heteroaryl” refers to an -(alkyl)heteroaryl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“alkyl-heteroaryl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heteroaryl” and“-(alkynyl)heteroaryl” mirror the above description of“-(alkyl)heteroaryl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Alkyl-heterocyclyl” refers to an -(alkyl)heterocyclyl radical wherealkyl and heterocyclyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“alkyl-heterocyclyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heterocyclyl” and“-(alkynyl)heterocyclyl” mirror the above description of“-(alkyl)heterocyclyl” wherein the term “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and “alkenyl” or “alkynyl” are asdescribed herein.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and in some embodiments, having from two to tencarbon atoms (i.e., C₂-C₁₀ alkenyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange; e.g., “2 to 10 carbon atoms” means that the alkenyl group canconsist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up toand including 10 carbon atoms. In certain embodiments, an alkenylcomprises two to eight carbon atoms. In other embodiments, an alkenylcomprises two to five carbon atoms (e.g., C₂-C₅ alkenyl). The alkenyl isattached to the parent molecular structure by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. The one or morecarbon-carbon double bonds can be internal (such as in 2-butenyl) orterminal (such as in 1-butenyl). Examples of C₂₋₄ alkenyl groups includeethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄),2-butenyl (C₄), butadienyl (C₄) and the like. Examples of C₂₋₆ alkenylgroups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless stated otherwise in the specification, analkenyl group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Alknyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having, in some embodiments, from two to tencarbon atoms (i.e., C₂-C₁₀ alkynyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange; e.g., “2 to 10 carbon atoms” means that the alkynyl group canconsist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up toand including 10 carbon atoms. In certain embodiments, an alkynylcomprises two to eight carbon atoms. In other embodiments, an alkynylhas two to five carbon atoms (e.g., C₂-C₅ alkynyl). The alkynyl isattached to the parent molecular structure by a single bond, forexample, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.Unless stated otherwise in the specification, an alkynyl group isoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkoxy” refers to the group —O-alkyl (in some embodiments,including from 1 to 10 carbon atoms), of a straight, branched, cyclicconfiguration and combinations thereof, attached to the parent molecularstructure through an oxygen. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. “Lower alkoxy”refers to alkoxy groups containing one to six carbons. In someembodiments, C₁-C₄ alkoxy is an alkoxy group which encompasses bothstraight and branched chain alkyls of from 1 to 4 carbon atoms. Unlessstated otherwise in the specification, an alkoxy group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxy” and “alkynoxy” mirror the above description of “alkoxy”wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon (in some embodiments, having from 1 to 10 carbon atoms).Thus a C₁-C₆ alkoxycarbonyl group comprises an alkoxy group having from1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.The C₁-C₆ designation does not include the carbonyl carbon in the atomcount. “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group whereinthe alkyl portion of the alkoxy group is a lower alkyl group. In someembodiments, C₁-C₄ alkoxycarbonyl comprises an alkoxy group whichencompasses both straight and branched chain alkoxy groups of from 1 to4 carbon atoms. Unless stated otherwise in the specification, analkoxycarbonyl group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxycarbonyl” and “alkynoxycarbonyl” mirror the above descriptionof “alkoxycarbonyl” wherein the prefix “alk” is replaced with “alken” or“alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to, H,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, provided herein is a C₁-C₁₀ acyl radical which refers tothe total number of chain or ring atoms of the, for example, alkyl,alkenyl, alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkylportion plus the carbonyl carbon of acyl. For example, a C₄-acyl hasthree other ring or chain atoms plus carbonyl. If the R radical isheteroaryl or heterocycloalkyl, the hetero ring or chain atomscontribute to the total number of chain or ring atoms. Unless statedotherwise in the specification, the “R” of an acyloxy group can beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be H, alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl, or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, e.g., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, 7-, or8-membered ring. For example, —N(R^(b))₂ is meant to include, but not belimited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise inthe specification, an amino group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

The terms “amine” and “amino” can also refer to N-oxides of the groups—N⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O⁻, where R^(a) is as describedabove, where the N-oxide is bonded to the parent molecular structurethrough the N atom. N-oxides can be prepared by treatment of thecorresponding amino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(b), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, an amido or amide radical is a C₁-C₄ amido or amideradical, which includes the amide carbonyl in the total number ofcarbons in the radical. When a —C(O)N(R^(b))₂ has two R^(b) other thanhydrogen, they can be combined with the nitrogen atom to form a 3-, 4-,5-, 6-, 7-, or 8-membered ring. For example, N(R^(b))₂ portion of a—C(O)N(R^(b))₂ radical is meant to include, but not be limited to,1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amido R^(b) group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 4th Ed., John Wiley &Sons, New York, N.Y., 2006, which is incorporated herein by reference inits entirety.

“Amidino” refers to the —C(═NR^(b))N(R^(b))₂, —N(R^(b))—C(═NR^(b))R^(b),and —N(R^(b))—C(═NR^(b))— radicals, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

“Aryl” refers to a radical with six to fourteen ring atoms (e.g., C₆-C₁₄or C₆-C₁₀ aryl) which has at least one carbocyclic ring having aconjugated pi electron system which is aromatic (e.g., having 6, 10, or14π electrons shared in a cyclic array) (e.g., phenyl, fluorenyl, andnaphthyl). In one embodiment, bivalent radicals formed from substitutedbenzene derivatives and having the free valences at ring atoms are namedas substituted phenylene radicals. In other embodiments, bivalentradicals derived from univalent monocyclic or polycyclic hydrocarbonradicals whose names end in “-yl” by removal of one hydrogen atom fromthe carbon atom with the free valence are named by adding “-idene” tothe name of the corresponding univalent radical, e.g., a naphthyl groupwith two points of attachment is termed naphthylidene. Whenever itappears herein, a numerical range such as “6 to 10 aryl” refers to eachinteger in the given range; e.g., “6 to 10 ring atoms” means that thearyl group can consist of 6 ring atoms, 7 ring atoms, etc., up to andincluding 10 ring atoms. The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of ring atoms)groups. Unless stated otherwise in the specification, an aryl moiety canbe optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. In oneembodiment, unless stated otherwise, “aryl” also includes ring systemswherein the aryl ring, as defined above, is fused with one or morecycloalkyl or heterocyclyl groups wherein the point of attachment to theparent molecular structure is on the aryl ring.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively. The “aralkyl” or “alylalkyl” is bonded tothe parent molecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

“Azide” refers to a —N₃ radical.

“Carbamate” refers to any of the following radicals: —O—(C═O)—N(R^(b))—,—O—(C═O)—N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))—(C═O)—OR^(b),wherein each R^(b) is independently selected from H, alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon), and heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Carbonate” refers to a —O—(C═O)—O— or —O—(C═O)—OR radical, where R canbe hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, aryl, cyclohexyl, heteroaryl, or heterocycloalkyl, whichare as described herein.

“Carbonyl” refers to a —(C═O)— radical.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl,” or alternatively, “carbocyclyl,” refers to a monocyclic orpolycyclic radical that contains only carbon and hydrogen, and can besaturated or partially unsaturated. Partially unsaturated cycloalkylgroups can be termed “cycloalkenyl” if the carbocycle contains at leastone double bond, or “cycloalkynyl” if the carbocycle contains at leastone triple bond. Cycloalkyl groups include groups having from 3 to 10ring atoms (e.g., C₃-C₁₀ cycloalkyl). Whenever it appears herein, anumerical range such as “3 to 10” refers to each integer in the givenrange; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group canconsist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up toand including 10 carbon atoms. The term “cycloalkyl” also includesbridged and spiro-fused cyclic structures containing no heteroatoms. Theterm also includes monocyclic or fused-ring polycyclic (i.e., ringswhich share adjacent pairs of ring atoms) groups. In some embodiments,it is a C₃-C₈ cycloalkyl radical. In some embodiments, it is a C₃-C₅cycloalkyl radical. Illustrative examples of cycloalkyl groups include,but are not limited to the following moieties: C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclobutyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆), and the like. Examples of C₃₋₈ carbocyclylgroups include the aforementioned C₃₋₆ carbocyclyl groups as well ascycloheptyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and thelike. Examples of C₃₋₁₀ carbocyclyl groups include the aforementionedC₃₋₈ carbocyclyl groups as well as octahydro-1H-indenyl,decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless statedotherwise in the specification, a cycloalkyl group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. In oneembodiment, unless stated otherwise, “cycloalkyl” or “carbocyclyl” alsoincludes ring systems wherein the cycloalkyl or carbocyclyl ring, asdefined above, is fused with one or more aryl or heteroaryl groupswherein the point of attachment to the parent molecular structure is onthe cycloalkyl or carbocyclyl ring.

“Cycloalkyl-alkyl” refers to a -(cycloalkyl)alkyl radical wherecycloalkyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkyl respectively. The“cycloalkyl-alkyl” is bonded to the parent molecular structure throughthe cycloalkyl group. The terms “cycloalkyl-alkenyl” and“cycloalkyl-alkynyl” mirror the above description of “cycloalkyl-alkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocyclylalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively. The “cycloalkyl-heterocycloalkyl” is bonded to the parentmolecular structure through the cycloalkyl group.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“cycloalkyl-heteroaryl” is bonded to the parent molecular structurethrough the cycloalkyl group.

As used herein, a “covalent bond” or “direct bond” refers to a singlebond joining two groups.

“Ester” refers to a radical of formula —COOR, where R is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon), and heteroarylalkyl. Any amine, hydroxy,or carboxyl side chain on the compounds described herein can beesterified. The procedures and specific groups to make such esters areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,4th Ed., John Wiley & Sons, New York, N.Y., 2006, which is incorporatedherein by reference in its entirety. Unless stated otherwise in thespecification, an ester group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ether” refers to a —R^(b)—O—R^(b) radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo, or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example can be up to 4 atomslong. For example, a —CH₂OCH₂CH₃ radical is referred to as a “C₄”heteroalkyl, which includes the heteroatom center in the atom chainlength description. Connection to the parent molecular structure can bethrough either a heteroatom or a carbon in the heteroalkyl chain Forexample, an N-containing heteroalkyl moiety refers to a group in whichat least one of the skeletal atoms is a nitrogen atom. One or moreheteroatom(s) in the heteroalkyl radical can be optionally oxidized. Oneor more nitrogen atoms, if present, can also be optionally quaternized.For example, heteroalkyl also includes skeletal chains substituted withone or more nitrogen oxide (—O—) substituents. Exemplary heteroalkylgroups include, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂—OCH₂OCH₃), (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃), and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃), and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃), and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroalkyl-aryl” refers to a -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively. The“heteroalkyl-aryl” is bonded to the parent molecular structure throughan atom of the heteroalkyl group.

“Heteroalkyl-heteroaryl” refers to a -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively. The“heteroalkyl-heteroaryl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroalkyl-heterocycloalkyl” refers to a-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl respectively. The“heteroalkyl-heterocycloalkyl” is bonded to the parent molecularstructure through an atom of the heteroalkyl group.

“Heteroalkyl-cycloalkyl” refers to a -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively. The“heteroalkyl-cycloalkyl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroaryl”, or alternatively, “heteroaromatic”, refers to a radical ofa 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic ortricyclic) aromatic ring system (e.g., having 6, 10 or 14π electronsshared in a cyclic array) having ring carbon atoms and 1 to 6 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5- to 18-membered heteroaryl”). Heteroaryl polycyclic ringsystems can include one or more heteroatoms in one or more rings.Whenever it appears herein, a numerical range such as “5 to 18” refersto each integer in the given range; e.g., “5 to 18 ring atoms” meansthat the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, 7ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to andincluding 18 ring atoms. In one embodiment, bivalent radicals derivedfrom univalent heteroaryl radicals whose names end in “-yl” by removalof one hydrogen atom from the atom with the free valence are named byadding “-idene” to the name of the corresponding univalent radical,e.g., a pyridyl group with two points of attachment is a pyridylidene.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quaternized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocyclyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl). In someembodiments, a heteroaryl group is a 5 to 10 membered aromatic ringsystem having ring carbon atoms and 1 to 4 ring heteroatoms provided inthe aromatic ring system, wherein each heteroatom is independentlyselected from nitrogen, oxygen, phosphorous, and sulfur (“5- to10-membered heteroaryl”). In some embodiments, a heteroaryl group is a5- to 8-membered aromatic ring system having ring carbon atoms and 1 to4 ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, aheteroaryl group is a 5- to 6-membered aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5- to 6-membered heteroaryl”). In someembodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatomsindependently selected from nitrogen, oxygen, phosphorous, and sulfur.In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ringheteroatoms independently selected from nitrogen, oxygen, phosphorous,and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl).

Unless stated otherwise in the specification, a heteroaryl moiety isoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocathonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroaryl-alkyl” refers to a -(heteroaryl)alkyl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“heteroaryl-alkyl” is bonded to the parent molecular structure throughany atom of the heteroaryl group.

“Heteroaryl-heterocycloalkyl” refers to an -(heteroaryl)heterocycloalkylradical where heteroaryl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heteroaryl and heterocycloalkylrespectively. The “heteroaryl-heterocycloalkyl” is bonded to the parentmolecular structure through an atom of the heteroaryl group.

“Heteroaryl-cycloalkyl” refers to an -(heteroaryl)cycloalkyl radicalwhere heteroaryl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“heteroaryl-cycloalkyl” is bonded to the parent molecular structurethrough a carbon atom of the heteroaryl group.

“Heterocyclyl”, “heterocycloalkyl” or “heterocarbocyclyl” each refer toany 3- to 18-membered non-aromatic radical monocyclic or polycyclicmoiety comprising at least one ring heteroatom selected from nitrogen,oxygen, phosphorous, and sulfur. A heterocyclyl group can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein thepolycyclic ring systems can be a fused, bridged or spiro ring system.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or more rings. A heterocyclyl group can be saturated or partiallyunsaturated. Partially unsaturated heterocycloalkyl groups can be termed“heterocycloalkenyl” if the heterocyclyl contains at least one doublebond, or “heterocycloalkynyl” if the heterocyclyl contains at least onetriple bond. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range; e.g., “5 to 18 ringatoms” means that the heterocyclyl group can consist of 5 ring atoms, 6ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms,etc., up to and including 18 ring atoms. In one embodiment, bivalentradicals derived from univalent heterocyclyl radicals whose names end in“-yl” by removal of one hydrogen atom from the atom with the freevalence are named by adding “-idene” to the name of the correspondingunivalent radical, e.g., a piperidyl group with two points of attachmentis a piperidylidene.

An N-containing heterocyclyl moiety refers to an non-aromatic group inwhich at least one of the ring atoms is a nitrogen atom. Theheteroatom(s) in the heterocyclyl radical can be optionally oxidized.One or more nitrogen atoms, if present, can be optionally quaternized.Heterocyclyl also includes ring systems substituted with one or morenitrogen oxide (—O—) substituents, such as piperidinyl N-oxides. Theheterocyclyl is attached to the parent molecular structure through anyatom of any of the ring(s).

“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment to the parent molecular structure is on the heterocyclylring. In some embodiments, a heterocyclyl group is a 3- to 10-memberednon-aromatic ring system having ring carbon atoms and 1 to 4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous, and sulfur (“3- to 10-memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to8-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous, and sulfur (“5- to 8-memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to6-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous, and sulfur (“5- to 6-memberedheterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclylhas 1 to 3 ring heteroatoms independently selected from nitrogen,oxygen, phosphorous, and sulfur. In some embodiments, the 5- to6-membered heterocyclyl has 1 to 2 ring heteroatoms independentlyselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatomselected from nitrogen, oxygen, phosphorous, and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromenyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R)₂, —N(R^(a))S(O)_(t)R^(a)(where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2),—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂, where eachR^(a) is independently hydrogen, alkyl, haloalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heterocyclyl-alkyl” refers to a -(heterocyclyl)alkyl radical whereheterocyclyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“heterocyclyl-alkyl” is bonded to the parent molecular structure throughany atom of the heterocyclyl group. The terms “heterocyclyl-alkenyl” and“heterocyclyl-alkynyl” mirror the above description of“heterocyclyl-alkyl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Imino” refers to the “—C(═N—R^(b))—R^(b)” radical where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphonate” refers to a —O—P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a —P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable non-limiting examples of suchgroups, unless otherwise specified, include halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, e.g., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Fourth Edition, John Wiley & Sons, New York (2006),incorporated herein by reference in its entirety. For example, a hydroxyprotected form is where at least one of the hydroxy groups present in acompound is protected with a hydroxy protecting group. Likewise, aminesand other reactive groups can similarly be protected.

As used herein, the terms “substituted” or “substitution” mean that atleast one hydrogen present on a group atom (e.g., a carbon or nitrogenatom) is replaced with a permissible substituent, e.g., a substituentwhich upon substitution for the hydrogen results in a stable compound,e.g., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, or other reaction.Unless otherwise indicated, a “substituted” group can have a substituentat one or more substitutable positions of the group, and when more thanone position in any given structure is substituted, the substituent iseither the same or different at each position. Substituents can includeone or more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), and —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. For example, acycloalkyl substituent can have a halide substituted at one or more ringcarbons, and the like. The protecting groups that can form theprotective derivatives of the above substituents are known to those ofskill in the art and can be found in references such as Greene and Wuts,above.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S—” radical, and “arylthio” refers to the “aryl-S—” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H, and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon), and heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon), and heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ or —N(R^(b))—S(═O)₂—R^(b) can be taken together withthe nitrogen to which they are attached to form a 4-, 5-, 6-, 7-, or8-membered heterocyclyl ring. In some embodiments, the term designates aC₁-C₄ sulfonamido, wherein each R^(b) in the sulfonamido contains 1carbon, 2 carbons, 3 carbons, or 4 carbons total.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon), and heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

Compounds

Provided herein are compounds of Formula I″:

or a pharmaceutically acceptable form thereof,

-   wherein R is halo, C₁-C₈ alkyl optionally substituted with one or    more halo, or

is a (5-14 membered fused bicyclic saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of N, O, and S) or (5-14 membered fused bicyclic saturated,unsaturated, or aromatic carbocycle); wherein the heterocycle orcarbocycle is optionally substituted with one or more substituentsselected from R^(2a), R^(3a), R^(4a), R^(6a), (R^(5a))_(n), and R^(1d);

-   n is 1, 2, or 3;-   L is a bond or —NR^(1e);-   W_(d) is selected from

-   X₁ is N or CR^(1f);-   X₂ is N or CR^(2f);-   X₃ is N or CR^(3f);-   X₄ is N or CR^(4f);-   X₅ is N or CR^(5f);-   each instance of R^(1a) is independently selected from the group    consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    OH, OR¹⁰, NH₂; NHR¹⁰, NR¹⁰R¹⁰, NR¹⁰COR¹⁰, COH, C(O)R¹⁰, COOH,    COOR¹⁰, CONH₂, CONHR¹⁰, CONR¹⁰R¹⁰, CN, halo, NO₂, haloalkyl, (3-14    membered saturated, unsaturated, or aromatic carbocycle), and (3-14    membered saturated, unsaturated, or aromatic heterocycle containing    one or more heteroatoms selected from the group consisting of N, O,    and S); wherein each of alkyl, alkenyl, alkynyl, haloalkyl,    carbocycle, or heterocycle is optionally substituted with one or    more R¹¹;-   each instance of R¹⁰ is independently selected from the group    consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    halo, OH, O(C₁-C₈ alkyl), NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂,    haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂,    COH, CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl),    N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated,    unsaturated, or aromatic carbocycle), and (3-14 membered saturated,    unsaturated, or aromatic heterocycle containing one or more    heteroatoms selected from the group consisting of N, O, and S);-   each instance of R¹¹ is independently selected from the group    consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl),    N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl),    CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl),    NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 membered    saturated, unsaturated, or aromatic carbocycle), and (3-14 membered    saturated, unsaturated, or aromatic heterocycle containing one or    more heteroatoms selected from the group consisting of N, O, and S);-   each instance of R^(2a), R^(3a), R^(4a), R^(5a), and R^(6a) is    independently selected from the group consisting of hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, oxo, OH, O(C₁-C₈ alkyl),    OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂,    haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂,    COH, CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl),    N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated,    unsaturated, or aromatic carbocycle), and (3-14 membered saturated,    unsaturated, or aromatic heterocycle containing one or more    heteroatoms selected from the group consisting of N, O, and S);-   R^(1b), R^(2b), R^(3b), R^(4b), and R^(5b) each is independently    selected from the group consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈    alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H,    OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂,    CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl),    COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈    alkyl), (3-14 membered saturated, unsaturated, or aromatic    carbocycle), and (3-14 membered saturated, unsaturated, or aromatic    heterocycle containing one or more heteroatoms selected from the    group consisting of N, O, and S);-   R^(1c) is selected from the group consisting of hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃,    OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN,    NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈    alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈    alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated, unsaturated, or    aromatic carbocycle), and (3-14 membered saturated, unsaturated, or    aromatic heterocycle containing one or more heteroatoms selected    from the group consisting of N, O, and S);-   R^(2c) is selected from the group consisting of hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃,    OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN,    NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈    alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈    alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated, unsaturated, or    aromatic carbocycle), and (3-14 membered saturated, unsaturated, or    aromatic heterocycle containing one or more heteroatoms selected    from the group consisting of N, O, and S); and-   R^(1d) is selected from the group consisting of hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl;-   R^(1e) is selected from the group consisting of hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl;-   R^(1f) is selected from the group consisting of NH₂, NH(C₁-C₈    alkyl), N(C₁-C₈ alkyl)₂, hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈    alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, haloalkyl,    CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈    alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈    alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated, unsaturated, or    aromatic carbocycle), and (3-14 membered saturated, unsaturated, or    aromatic heterocycle containing one or more heteroatoms selected    from the group consisting of N, O, and S); and-   R^(2f), R^(3f), R^(4f), and R^(5f) each is independently selected    from the group consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,    C₂-C₈ alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, NH₂,    NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂, CONH₂,    CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH,    COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl),    (3-14 membered saturated, unsaturated, or aromatic carbocycle), and    (3-14 membered saturated, unsaturated, or aromatic heterocycle    containing one or more heteroatoms selected from the group    consisting of N, O, and S);-   provided that W_(d) is not

and

-   provided that when W_(d) is

then R^(2f) is not hydrogen.

In one embodiment, R is halo. In one embodiment, R is F, Cl, Br, or I.In one embodiment, R is Cl.

In one embodiment, R is C₁-C₈ alkyl optionally substituted with one ormore halo. In one embodiment, R is methyl. In one embodiment, R is CF₃.

In one embodiment, R is

In one embodiment, provided herein is a compound of Formula I′:

or a pharmaceutically acceptable form thereof.

In one embodiment, none of X₂, X₃, X₄, and X₅ is N.

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, one of X₃, X₄, and X₅ is N, and X₂ is CR^(2f).

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, two of X₂, X₃, X₄, and X₅ are N.

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, three of X₂, X₃, X₄, and X₅ are N.

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, all of X₂, X₃, X₄, and X₅ are N.

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, W_(d) is

In one embodiment, the compound of Formula I′ is a compound of formulaI:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(1f) is NH₂, NH(C₁-C₈ alkyl), or N(C₁-C₈ alkyl)₂.In one embodiment, R^(1f) is NH₂. In one embodiment, R^(2f), R^(3f), andR^(4f) each is independently selected from the group consisting ofhydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂,haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH,CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), and N(C₁-C₈alkyl)CO(C₁-C₈ alkyl). In one embodiment, R^(2f), R^(3f), and R^(4f)each is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl. In one embodiment, R^(2f), R^(3f), and R^(4f) are hydrogen.

In one embodiment,

is a (8-10 membered fused bicyclic saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of N, O, and S) or (8-10 membered fused bicyclic saturated,unsaturated, or aromatic carbocycle).

In one embodiment, A is 6-membered heterocycle or carbocycle and B is6-membered heterocycle or carbocycle. In one embodiment, A is 6-memberedheterocycle and B is 6-membered carbocycle. In one embodiment, A is6-membered heterocycle and B is 6-membered heterocycle.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(2a), R^(3a), and R^(4a) each is independentlyhydrogen, C₁-C₈ alkyl, or halo. In one embodiment, R^(2a), R^(3a), andR^(4a) are hydrogen. In one embodiment, R^(2a) is halo, and R^(3a) andR^(4a) are hydrogen.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(2a), R^(3a), and R^(4a) each is independentlyhydrogen, C₁-C₈ alkyl, or halo. In one embodiment, R^(2a), R^(3a), andR^(4a) are hydrogen. In one embodiment, R^(2a) is halo, and R^(3a) andR^(4a) are hydrogen.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(2a), R^(3a), and R^(4a) each is independentlyhydrogen, C₁-C₈ alkyl, or halo. In one embodiment, R^(2a), R^(3a), andR^(4a) are hydrogen. In one embodiment, R^(2a) is halo, and R^(3a) andR^(4a) are hydrogen.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(2a), R^(3a), and R^(4a) each is independentlyhydrogen, C₁-C₈ alkyl, or halo. In one embodiment, R^(2a), R^(3a), andR^(4a) are hydrogen. In one embodiment, R^(2a) is halo, and R^(3a) andR^(4a) are hydrogen.

In one embodiment, A is 6-membered heterocycle or carbocycle and B is5-membered heterocycle or carbocycle. In one embodiment, A is 6-memberedheterocycle and B is 5-membered heterocycle. In one embodiment, A is6-membered heterocycle and B is 5-membered carbocycle.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(2a) and R^(3a) each is independently hydrogen,C₁-C₈ alkyl, or halo. In one embodiment, R^(2a) and R^(3a) are hydrogen.In one embodiment, R^(2a) is halo, and R^(3a) is hydrogen.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(2a) is hydrogen, C₁-C₈ alkyl, or halo. In oneembodiment, R^(2a) is hydrogen. In one embodiment, R^(2a) is halo.

In one embodiment, A is 5-membered heterocycle or carbocycle and B is6-membered heterocycle or carbocycle. In one embodiment, A is 5-memberedheterocycle and B is 6-membered heterocycle. In one embodiment, A is5-membered heterocycle and B is 6-membered carbocycle.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, R^(1d) is hydrogen or C₁-C₈ alkyl. In one embodiment,R^(1d) is hydrogen. In one embodiment, R^(1d) is methyl. In oneembodiment, each instance of R^(5a) is independently hydrogen, C₁-C₈alkyl, or halo. In one embodiment, each instance of R^(5a) isindependently hydrogen. In one embodiment, n is 1. In one embodiment, nis 2. In one embodiment, n is 3.

In one embodiment, A is 5-membered heterocycle or carbocycle and B is5-membered heterocycle or carbocycle. In one embodiment, A is 5-memberedheterocycle and B is 5-membered heterocycle.

In one embodiment,

In one embodiment,

In one embodiment, the compound of Formula I′ is a compound of theformula:

or a pharmaceutically acceptable form thereof.

In one embodiment, each instance of R^(5a) is independently hydrogen,C₁-C₈ alkyl, or halo. In one embodiment, R^(5a) is hydrogen. In oneembodiment, R^(1a) is hydrogen, C₁-C₈ alkyl, or 3-14 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of N, O, and S.

In one embodiment, R^(1a) is C₁-C₈ alkyl. In one embodiment, R^(1a) is3-14 membered saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of N, O, andS. In one embodiment, R^(1a) is 5- or 6-membered aromatic heterocyclecontaining one or more N heteroatoms.

In some embodiments, R^(1a) is: methyl,

In one embodiment, the heterocycle is optionally substituted with one ormore C₁-C₈ alkyl. In one embodiment, R^(1b), R², R^(3b), R^(4b), andR^(5b) are hydrogen.

In one embodiment, R^(1c) is C₁-C₈ alkyl. In one embodiment, R^(1c) ismethyl. In one embodiment, R^(2c) is hydrogen or C₁-C₈ alkyl. In oneembodiment, R^(2c) is hydrogen.

In one embodiment, the compound of Formula I″ has an S-configuration atthe carbon chiral center connected to R^(1c), N—R^(2c), and Ring A. Inone embodiment, the compound of Formula I″ is a compound of FormulaI″-S. Exemplary compounds are listed in Table 1, Table 2, Table 3, andTable 4, including a pharmaceutically acceptable form thereof.

TABLE 1 Formula I″-S

COMPOUND A-B CORE R WD   1 CORE-1  R-1 WD-1    2 CORE-1  R-1 WD-2    3CORE-1  R-1 WD-3    4 CORE-1  R-1 WD-4    5 CORE-1  R-1 WD-5    6CORE-1  R-1 WD-6    7 CORE-1  R-1 WD-7    8 CORE-1  R-1 WD-8    9CORE-1  R-1 WD-9   10 CORE-1  R-1 WD-10  11 CORE-1  R-2 WD-1   12CORE-1  R-2 WD-2   13 CORE-1  R-2 WD-3   14 CORE-1  R-2 WD-4   15CORE-1  R-2 WD-5   16 CORE-1  R-2 WD-6   17 CORE-1  R-2 WD-7   18CORE-1  R-2 WD-8   19 CORE-1  R-2 WD-9   20 CORE-1  R-2 WD-10  21CORE-1  R-3 WD-1   22 CORE-1  R-3 WD-2   23 CORE-1  R-3 WD-3   24CORE-1  R-3 WD-4   25 CORE-1  R-3 WD-5   26 CORE-1  R-3 WD-6   27CORE-1  R-3 WD-7   28 CORE-1  R-3 WD-8   29 CORE-1  R-3 WD-9   30CORE-1  R-3 WD-10  31 CORE-1  R-4 WD-1   32 CORE-1  R-4 WD-2   33CORE-1  R-4 WD-3   34 CORE-1  R-4 WD-4   35 CORE-1  R-4 WD-5   36CORE-1  R-4 WD-6   37 CORE-1  R-4 WD-7   38 CORE-1  R-4 WD-8   39CORE-1  R-4 WD-9   40 CORE-1  R-4 WD-10  41 CORE-1  R-5 WD-1   42CORE-1  R-5 WD-2   43 CORE-1  R-5 WD-3   44 CORE-1  R-5 WD-4   45CORE-1  R-5 WD-5   46 CORE-1  R-5 WD-6   47 CORE-1  R-5 WD-7   48CORE-1  R-5 WD-8   49 CORE-1  R-5 WD-9   50 CORE-1  R-5 WD-10  51CORE-2  R-1 WD-1   52 CORE-2  R-1 WD-2   53 CORE-2  R-1 WD-3   54CORE-2  R-1 WD-4   55 CORE-2  R-1 WD-5   56 CORE-2  R-1 WD-6   57CORE-2  R-1 WD-7   58 CORE-2  R-1 WD-8   59 CORE-2  R-1 WD-9   60CORE-2  R-1 WD-10  61 CORE-2  R-2 WD-1   62 CORE-2  R-2 WD-2   63CORE-2  R-2 WD-3   64 CORE-2  R-2 WD-4   65 CORE-2  R-2 WD-5   66CORE-2  R-2 WD-6   67 CORE-2  R-2 WD-7   68 CORE-2  R-2 WD-8   69CORE-2  R-2 WD-9   70 CORE-2  R-2 WD-10  71 CORE-2  R-3 WD-1   72CORE-2  R-3 WD-2   73 CORE-2  R-3 WD-3   74 CORE-2  R-3 WD-4   75CORE-2  R-3 WD-5   76 CORE-2  R-3 WD-6   77 CORE-2  R-3 WD-7   78CORE-2  R-3 WD-8   79 CORE-2  R-3 WD-9   80 CORE-2  R-3 WD-10  81CORE-2  R-4 WD-1   82 CORE-2  R-4 WD-2   83 CORE-2  R-4 WD-3   84CORE-2  R-4 WD-4   85 CORE-2  R-4 WD-5   86 CORE-2  R-4 WD-6   87CORE-2  R-4 WD-7   88 CORE-2  R-4 WD-8   89 CORE-2  R-4 WD-9   90CORE-2  R-4 WD-10  91 CORE-2  R-5 WD-1   92 CORE-2  R-5 WD-2   93CORE-2  R-5 WD-3   94 CORE-2  R-5 WD-4   95 CORE-2  R-5 WD-5   96CORE-2  R-5 WD-6   97 CORE-2  R-5 WD-7   98 CORE-2  R-5 WD-8   99CORE-2  R-5 WD-9   100 CORE-2  R-5 WD-10  101 CORE-3  R-1 WD-1   102CORE-3  R-1 WD-2   103 CORE-3  R-1 WD-3   104 CORE-3  R-1 WD-4   105CORE-3  R-1 WD-5   106 CORE-3  R-1 WD-6   107 CORE-3  R-1 WD-7   108CORE-3  R-1 WD-8   109 CORE-3  R-1 WD-9   110 CORE-3  R-1 WD-10  111CORE-3  R-2 WD-1   112 CORE-3  R-2 WD-2   113 CORE-3  R-2 WD-3   114CORE-3  R-2 WD-4   115 CORE-3  R-2 WD-5   116 CORE-3  R-2 WD-6   117CORE-3  R-2 WD-7   118 CORE-3  R-2 WD-8   119 CORE-3  R-2 WD-9   120CORE-3  R-2 WD-10  121 CORE-3  R-3 WD-1   122 CORE-3  R-3 WD-2   123CORE-3  R-3 WD-3   124 CORE-3  R-3 WD-4   125 CORE-3  R-3 WD-5   126CORE-3  R-3 WD-6   127 CORE-3  R-3 WD-7   128 CORE-3  R-3 WD-8   129CORE-3  R-3 WD-9   130 CORE-3  R-3 WD-10  131 CORE-3  R-4 WD-1   132CORE-3  R-4 WD-2   133 CORE-3  R-4 WD-3   134 CORE-3  R-4 WD-4   135CORE-3  R-4 WD-5   136 CORE-3  R-4 WD-6   137 CORE-3  R-4 WD-7   138CORE-3  R-4 WD-8   139 CORE-3  R-4 WD-9   140 CORE-3  R-4 WD-10  141CORE-3  R-5 WD-1   142 CORE-3  R-5 WD-2   143 CORE-3  R-5 WD-3   144CORE-3  R-5 WD-4   145 CORE-3  R-5 WD-5   146 CORE-3  R-5 WD-6   147CORE-3  R-5 WD-7   148 CORE-3  R-5 WD-8   149 CORE-3  R-5 WD-9   150CORE-3  R-5 WD-10  151 CORE-4  R-1 WD-1   152 CORE-4  R-1 WD-2   153CORE-4  R-1 WD-3   154 CORE-4  R-1 WD-4   155 CORE-4  R-1 WD-5   156CORE-4  R-1 WD-6   157 CORE-4  R-1 WD-7   158 CORE-4  R-1 WD-8   159CORE-4  R-1 WD-9   160 CORE-4  R-1 WD-10  161 CORE-4  R-2 WD-1   162CORE-4  R-2 WD-2   163 CORE-4  R-2 WD-3   164 CORE-4  R-2 WD-4   165CORE-4  R-2 WD-5   166 CORE-4  R-2 WD-6   167 CORE-4  R-2 WD-7   168CORE-4  R-2 WD-8   169 CORE-4  R-2 WD-9   170 CORE-4  R-2 WD-10  171CORE-4  R-3 WD-1   172 CORE-4  R-3 WD-2   173 CORE-4  R-3 WD-3   174CORE-4  R-3 WD-4   175 CORE-4  R-3 WD-5   176 CORE-4  R-3 WD-6   177CORE-4  R-3 WD-7   178 CORE-4  R-3 WD-8   179 CORE-4  R-3 WD-9   180CORE-4  R-3 WD-10  181 CORE-4  R-4 WD-1   182 CORE-4  R-4 WD-2   183CORE-4  R-4 WD-3   184 CORE-4  R-4 WD-4   185 CORE-4  R-4 WD-5   186CORE-4  R-4 WD-6   187 CORE-4  R-4 WD-7   188 CORE-4  R-4 WD-8   189CORE-4  R-4 WD-9   190 CORE-4  R-4 WD-10  191 CORE-4  R-5 WD-1   192CORE-4  R-5 WD-2   193 CORE-4  R-5 WD-3   194 CORE-4  R-5 WD-4   195CORE-4  R-5 WD-5   196 CORE-4  R-5 WD-6   197 CORE-4  R-5 WD-7   198CORE-4  R-5 WD-8   199 CORE-4  R-5 WD-9   200 CORE-4  R-5 WD-10  201CORE-5  R-1 WD-1   202 CORE-5  R-1 WD-2   203 CORE-5  R-1 WD-3   204CORE-5  R-1 WD-4   205 CORE-5  R-1 WD-5   206 CORE-5  R-1 WD-6   207CORE-5  R-1 WD-7   208 CORE-5  R-1 WD-8   209 CORE-5  R-1 WD-9   210CORE-5  R-1 WD-10  211 CORE-5  R-2 WD-1   212 CORE-5  R-2 WD-2   213CORE-5  R-2 WD-3   214 CORE-5  R-2 WD-4   215 CORE-5  R-2 WD-5   216CORE-5  R-2 WD-6   217 CORE-5  R-2 WD-7   218 CORE-5  R-2 WD-8   219CORE-5  R-2 WD-9   220 CORE-5  R-2 WD-10  221 CORE-5  R-3 WD-1   222CORE-5  R-3 WD-2   223 CORE-5  R-3 WD-3   224 CORE-5  R-3 WD-4   225CORE-5  R-3 WD-5   226 CORE-5  R-3 WD-6   227 CORE-5  R-3 WD-7   228CORE-5  R-3 WD-8   229 CORE-5  R-3 WD-9   230 CORE-5  R-3 WD-10  231CORE-5  R-4 WD-1   232 CORE-5  R-4 WD-2   233 CORE-5  R-4 WD-3   234CORE-5  R-4 WD-4   235 CORE-5  R-4 WD-5   236 CORE-5  R-4 WD-6   237CORE-5  R-4 WD-7   238 CORE-5  R-4 WD-8   239 CORE-5  R-4 WD-9   240CORE-5  R-4 WD-10  241 CORE-5  R-5 WD-1   242 CORE-5  R-5 WD-2   243CORE-5  R-5 WD-3   244 CORE-5  R-5 WD-4   245 CORE-5  R-5 WD-5   246CORE-5  R-5 WD-6   247 CORE-5  R-5 WD-7   248 CORE-5  R-5 WD-8   249CORE-5  R-5 WD-9   250 CORE-5  R-5 WD-10  251 CORE-6  R-1 WD-1   252CORE-6  R-1 WD-2   253 CORE-6  R-1 WD-3   254 CORE-6  R-1 WD-4   255CORE-6  R-1 WD-5   256 CORE-6  R-1 WD-6   257 CORE-6  R-1 WD-7   258CORE-6  R-1 WD-8   259 CORE-6  R-1 WD-9   260 CORE-6  R-1 WD-10  261CORE-6  R-2 WD-1   262 CORE-6  R-2 WD-2   263 CORE-6  R-2 WD-3   264CORE-6  R-2 WD-4   265 CORE-6  R-2 WD-5   266 CORE-6  R-2 WD-6   267CORE-6  R-2 WD-7   268 CORE-6  R-2 WD-8   269 CORE-6  R-2 WD-9   270CORE-6  R-2 WD-10  271 CORE-6  R-3 WD-1   272 CORE-6  R-3 WD-2   273CORE-6  R-3 WD-3   274 CORE-6  R-3 WD-4   275 CORE-6  R-3 WD-5   276CORE-6  R-3 WD-6   277 CORE-6  R-3 WD-7   278 CORE-6  R-3 WD-8   279CORE-6  R-3 WD-9   280 CORE-6  R-3 WD-10  281 CORE-6  R-4 WD-1   282CORE-6  R-4 WD-2   283 CORE-6  R-4 WD-3   284 CORE-6  R-4 WD-4   285CORE-6  R-4 WD-5   286 CORE-6  R-4 WD-6   287 CORE-6  R-4 WD-7   288CORE-6  R-4 WD-8   289 CORE-6  R-4 WD-9   290 CORE-6  R-4 WD-10  291CORE-6  R-5 WD-1   292 CORE-6  R-5 WD-2   293 CORE-6  R-5 WD-3   294CORE-6  R-5 WD-4   295 CORE-6  R-5 WD-5   296 CORE-6  R-5 WD-6   297CORE-6  R-5 WD-7   298 CORE-6  R-5 WD-8   299 CORE-6  R-5 WD-9   300CORE-6  R-5 WD-10  301 CORE-7  R-1 WD-1   302 CORE-7  R-1 WD-2   303CORE-7  R-1 WD-3   304 CORE-7  R-1 WD-4   305 CORE-7  R-1 WD-5   306CORE-7  R-1 WD-6   307 CORE-7  R-1 WD-7   308 CORE-7  R-1 WD-8   309CORE-7  R-1 WD-9   310 CORE-7  R-1 WD-10  311 CORE-7  R-2 WD-1   312CORE-7  R-2 WD-2   313 CORE-7  R-2 WD-3   314 CORE-7  R-2 WD-4   315CORE-7  R-2 WD-5   316 CORE-7  R-2 WD-6   317 CORE-7  R-2 WD-7   318CORE-7  R-2 WD-8   319 CORE-7  R-2 WD-9   320 CORE-7  R-2 WD-10  321CORE-7  R-3 WD-1   322 CORE-7  R-3 WD-2   323 CORE-7  R-3 WD-3   324CORE-7  R-3 WD-4   325 CORE-7  R-3 WD-5   326 CORE-7  R-3 WD-6   327CORE-7  R-3 WD-7   328 CORE-7  R-3 WD-8   329 CORE-7  R-3 WD-9   330CORE-7  R-3 WD-10  331 CORE-7  R-4 WD-1   332 CORE-7  R-4 WD-2   333CORE-7  R-4 WD-3   334 CORE-7  R-4 WD-4   335 CORE-7  R-4 WD-5   336CORE-7  R-4 WD-6   337 CORE-7  R-4 WD-7   338 CORE-7  R-4 WD-8   339CORE-7  R-4 WD-9   340 CORE-7  R-4 WD-10  341 CORE-7  R-5 WD-1   342CORE-7  R-5 WD-2   343 CORE-7  R-5 WD-3   344 CORE-7  R-5 WD-4   345CORE-7  R-5 WD-5   346 CORE-7  R-5 WD-6   347 CORE-7  R-5 WD-7   348CORE-7  R-5 WD-8   349 CORE-7  R-5 WD-9   350 CORE-7  R-5 WD-10  351CORE-8  R-1 WD-1   352 CORE-8  R-1 WD-2   353 CORE-8  R-1 WD-3   354CORE-8  R-1 WD-4   355 CORE-8  R-1 WD-5   356 CORE-8  R-1 WD-6   357CORE-8  R-1 WD-7   358 CORE-8  R-1 WD-8   359 CORE-8  R-1 WD-9   360CORE-8  R-1 WD-10  361 CORE-8  R-2 WD-1   362 CORE-8  R-2 WD-2   363CORE-8  R-2 WD-3   364 CORE-8  R-2 WD-4   365 CORE-8  R-2 WD-5   366CORE-8  R-2 WD-6   367 CORE-8  R-2 WD-7   368 CORE-8  R-2 WD-8   369CORE-8  R-2 WD-9   370 CORE-8  R-2 WD-10  371 CORE-8  R-3 WD-1   372CORE-8  R-3 WD-2   373 CORE-8  R-3 WD-3   374 CORE-8  R-3 WD-4   375CORE-8  R-3 WD-5   376 CORE-8  R-3 WD-6   377 CORE-8  R-3 WD-7   378CORE-8  R-3 WD-8   379 CORE-8  R-3 WD-9   380 CORE-8  R-3 WD-10  381CORE-8  R-4 WD-1   382 CORE-8  R-4 WD-2   383 CORE-8  R-4 WD-3   384CORE-8  R-4 WD-4   385 CORE-8  R-4 WD-5   386 CORE-8  R-4 WD-6   387CORE-8  R-4 WD-7   388 CORE-8  R-4 WD-8   389 CORE-8  R-4 WD-9   390CORE-8  R-4 WD-10  391 CORE-8  R-5 WD-1   392 CORE-8  R-5 WD-2   393CORE-8  R-5 WD-3   394 CORE-8  R-5 WD-4   395 CORE-8  R-5 WD-5   396CORE-8  R-5 WD-6   397 CORE-8  R-5 WD-7   398 CORE-8  R-5 WD-8   399CORE-8  R-5 WD-9   400 CORE-8  R-5 WD-10  401 CORE-9  R-1 WD-1   402CORE-9  R-1 WD-2   403 CORE-9  R-1 WD-3   404 CORE-9  R-1 WD-4   405CORE-9  R-1 WD-5   406 CORE-9  R-1 WD-6   407 CORE-9  R-1 WD-7   408CORE-9  R-1 WD-8   409 CORE-9  R-1 WD-9   410 CORE-9  R-1 WD-10  411CORE-9  R-2 WD-1   412 CORE-9  R-2 WD-2   413 CORE-9  R-2 WD-3   414CORE-9  R-2 WD-4   415 CORE-9  R-2 WD-5   416 CORE-9  R-2 WD-6   417CORE-9  R-2 WD-7   418 CORE-9  R-2 WD-8   419 CORE-9  R-2 WD-9   420CORE-9  R-2 WD-10  421 CORE-9  R-3 WD-1   422 CORE-9  R-3 WD-2   423CORE-9  R-3 WD-3   424 CORE-9  R-3 WD-4   425 CORE-9  R-3 WD-5   426CORE-9  R-3 WD-6   427 CORE-9  R-3 WD-7   428 CORE-9  R-3 WD-8   429CORE-9  R-3 WD-9   430 CORE-9  R-3 WD-10  431 CORE-9  R-4 WD-1   432CORE-9  R-4 WD-2   433 CORE-9  R-4 WD-3   434 CORE-9  R-4 WD-4   435CORE-9  R-4 WD-5   436 CORE-9  R-4 WD-6   437 CORE-9  R-4 WD-7   438CORE-9  R-4 WD-8   439 CORE-9  R-4 WD-9   440 CORE-9  R-4 WD-10  441CORE-9  R-5 WD-1   442 CORE-9  R-5 WD-2   443 CORE-9  R-5 WD-3   444CORE-9  R-5 WD-4   445 CORE-9  R-5 WD-5   446 CORE-9  R-5 WD-6   447CORE-9  R-5 WD-7   448 CORE-9  R-5 WD-8   449 CORE-9  R-5 WD-9   450CORE-9  R-5 WD-10  451 CORE-10 R-1 WD-1   452 CORE-10 R-1 WD-2   453CORE-10 R-1 WD-3   454 CORE-10 R-1 WD-4   455 CORE-10 R-1 WD-5   456CORE-10 R-1 WD-6   457 CORE-10 R-1 WD-7   458 CORE-10 R-1 WD-8   459CORE-10 R-1 WD-9   460 CORE-10 R-1 WD-10  461 CORE-10 R-2 WD-1   462CORE-10 R-2 WD-2   463 CORE-10 R-2 WD-3   464 CORE-10 R-2 WD-4   465CORE-10 R-2 WD-5   466 CORE-10 R-2 WD-6   467 CORE-10 R-2 WD-7   468CORE-10 R-2 WD-8   469 CORE-10 R-2 WD-9   470 CORE-10 R-2 WD-10  471CORE-10 R-3 WD-1   472 CORE-10 R-3 WD-2   473 CORE-10 R-3 WD-3   474CORE-10 R-3 WD-4   475 CORE-10 R-3 WD-5   476 CORE-10 R-3 WD-6   477CORE-10 R-3 WD-7   478 CORE-10 R-3 WD-8   479 CORE-10 R-3 WD-9   480CORE-10 R-3 WD-10  481 CORE-10 R-4 WD-1   482 CORE-10 R-4 WD-2   483CORE-10 R-4 WD-3   484 CORE-10 R-4 WD-4   485 CORE-10 R-4 WD-5   486CORE-10 R-4 WD-6   487 CORE-10 R-4 WD-7   488 CORE-10 R-4 WD-8   489CORE-10 R-4 WD-9   490 CORE-10 R-4 WD-10  491 CORE-10 R-5 WD-1   492CORE-10 R-5 WD-2   493 CORE-10 R-5 WD-3   494 CORE-10 R-5 WD-4   495CORE-10 R-5 WD-5   496 CORE-10 R-5 WD-6   497 CORE-10 R-5 WD-7   498CORE-10 R-5 WD-8   499 CORE-10 R-5 WD-9   500 CORE-10 R-5 WD-10  501CORE-11 R-1 WD-1   502 CORE-11 R-1 WD-2   503 CORE-11 R-1 WD-3   504CORE-11 R-1 WD-4   505 CORE-11 R-1 WD-5   506 CORE-11 R-1 WD-6   507CORE-11 R-1 WD-7   508 CORE-11 R-1 WD-8   509 CORE-11 R-1 WD-9   510CORE-11 R-1 WD-10  511 CORE-11 R-2 WD-1   512 CORE-11 R-2 WD-2   513CORE-11 R-2 WD-3   514 CORE-11 R-2 WD-4   515 CORE-11 R-2 WD-5   516CORE-11 R-2 WD-6   517 CORE-11 R-2 WD-7   518 CORE-11 R-2 WD-8   519CORE-11 R-2 WD-9   520 CORE-11 R-2 WD-10  521 CORE-11 R-3 WD-1   522CORE-11 R-3 WD-2   523 CORE-11 R-3 WD-3   524 CORE-11 R-3 WD-4   525CORE-11 R-3 WD-5   526 CORE-11 R-3 WD-6   527 CORE-11 R-3 WD-7   528CORE-11 R-3 WD-8   529 CORE-11 R-3 WD-9   530 CORE-11 R-3 WD-10  531CORE-11 R-4 WD-1   532 CORE-11 R-4 WD-2   533 CORE-11 R-4 WD-3   534CORE-11 R-4 WD-4   535 CORE-11 R-4 WD-5   536 CORE-11 R-4 WD-6   537CORE-11 R-4 WD-7   538 CORE-11 R-4 WD-8   539 CORE-11 R-4 WD-9   540CORE-11 R-4 WD-10  541 CORE-11 R-5 WD-1   542 CORE-11 R-5 WD-2   543CORE-11 R-5 WD-3   544 CORE-11 R-5 WD-4   545 CORE-11 R-5 WD-5   546CORE-11 R-5 WD-6   547 CORE-11 R-5 WD-7   548 CORE-11 R-5 WD-8   549CORE-11 R-5 WD-9   550 CORE-11 R-5 WD-10  551 CORE-12 R-1 WD-1   552CORE-12 R-1 WD-2   553 CORE-12 R-1 WD-3   554 CORE-12 R-1 WD-4   555CORE-12 R-1 WD-5   556 CORE-12 R-1 WD-6   557 CORE-12 R-1 WD-7   558CORE-12 R-1 WD-8   559 CORE-12 R-1 WD-9   560 CORE-12 R-1 WD-10  561CORE-12 R-2 WD-1   562 CORE-12 R-2 WD-2   563 CORE-12 R-2 WD-3   564CORE-12 R-2 WD-4   565 CORE-12 R-2 WD-5   566 CORE-12 R-2 WD-6   567CORE-12 R-2 WD-7   568 CORE-12 R-2 WD-8   569 CORE-12 R-2 WD-9   570CORE-12 R-2 WD-10  571 CORE-12 R-3 WD-1   572 CORE-12 R-3 WD-2   573CORE-12 R-3 WD-3   574 CORE-12 R-3 WD-4   575 CORE-12 R-3 WD-5   576CORE-12 R-3 WD-6   577 CORE-12 R-3 WD-7   578 CORE-12 R-3 WD-8   579CORE-12 R-3 WD-9   580 CORE-12 R-3 WD-10  581 CORE-12 R-4 WD-1   582CORE-12 R-4 WD-2   583 CORE-12 R-4 WD-3   584 CORE-12 R-4 WD-4   585CORE-12 R-4 WD-5   586 CORE-12 R-4 WD-6   587 CORE-12 R-4 WD-7   588CORE-12 R-4 WD-8   589 CORE-12 R-4 WD-9   590 CORE-12 R-4 WD-10  591CORE-12 R-5 WD-1   592 CORE-12 R-5 WD-2   593 CORE-12 R-5 WD-3   594CORE-12 R-5 WD-4   595 CORE-12 R-5 WD-5   596 CORE-12 R-5 WD-6   597CORE-12 R-5 WD-7   598 CORE-12 R-5 WD-8   599 CORE-12 R-5 WD-9   600CORE-12 R-5 WD-10  601 CORE-13 R-1 WD-1   602 CORE-13 R-1 WD-2   603CORE-13 R-1 WD-3   604 CORE-13 R-1 WD-4   605 CORE-13 R-1 WD-5   606CORE-13 R-1 WD-6   607 CORE-13 R-1 WD-7   608 CORE-13 R-1 WD-8   609CORE-13 R-1 WD-9   610 CORE-13 R-1 WD-10  611 CORE-13 R-2 WD-1   612CORE-13 R-2 WD-2   613 CORE-13 R-2 WD-3   614 CORE-13 R-2 WD-4   615CORE-13 R-2 WD-5   616 CORE-13 R-2 WD-6   617 CORE-13 R-2 WD-7   618CORE-13 R-2 WD-8   619 CORE-13 R-2 WD-9   620 CORE-13 R-2 WD-10  621CORE-13 R-3 WD-1   622 CORE-13 R-3 WD-2   623 CORE-13 R-3 WD-3   624CORE-13 R-3 WD-4   625 CORE-13 R-3 WD-5   626 CORE-13 R-3 WD-6   627CORE-13 R-3 WD-7   628 CORE-13 R-3 WD-8   629 CORE-13 R-3 WD-9   630CORE-13 R-3 WD-10  631 CORE-13 R-4 WD-1   632 CORE-13 R-4 WD-2   633CORE-13 R-4 WD-3   634 CORE-13 R-4 WD-4   635 CORE-13 R-4 WD-5   636CORE-13 R-4 WD-6   637 CORE-13 R-4 WD-7   638 CORE-13 R-4 WD-8   639CORE-13 R-4 WD-9   640 CORE-13 R-4 WD-10  641 CORE-13 R-5 WD-1   642CORE-13 R-5 WD-2   643 CORE-13 R-5 WD-3   644 CORE-13 R-5 WD-4   645CORE-13 R-5 WD-5   646 CORE-13 R-5 WD-6   647 CORE-13 R-5 WD-7   648CORE-13 R-5 WD-8   649 CORE-13 R-5 WD-9   650 CORE-13 R-5 WD-10  651CORE-14 R-1 WD-1   652 CORE-14 R-1 WD-2   653 CORE-14 R-1 WD-3   654CORE-14 R-1 WD-4   655 CORE-14 R-1 WD-5   656 CORE-14 R-1 WD-6   657CORE-14 R-1 WD-7   658 CORE-14 R-1 WD-8   659 CORE-14 R-1 WD-9   660CORE-14 R-1 WD-10  661 CORE-14 R-2 WD-1   662 CORE-14 R-2 WD-2   663CORE-14 R-2 WD-3   664 CORE-14 R-2 WD-4   665 CORE-14 R-2 WD-5   666CORE-14 R-2 WD-6   667 CORE-14 R-2 WD-7   668 CORE-14 R-2 WD-8   669CORE-14 R-2 WD-9   670 CORE-14 R-2 WD-10  671 CORE-14 R-3 WD-1   672CORE-14 R-3 WD-2   673 CORE-14 R-3 WD-3   674 CORE-14 R-3 WD-4   675CORE-14 R-3 WD-5   676 CORE-14 R-3 WD-6   677 CORE-14 R-3 WD-7   678CORE-14 R-3 WD-8   679 CORE-14 R-3 WD-9   680 CORE-14 R-3 WD-10  681CORE-14 R-4 WD-1   682 CORE-14 R-4 WD-2   683 CORE-14 R-4 WD-3   684CORE-14 R-4 WD-4   685 CORE-14 R-4 WD-5   686 CORE-14 R-4 WD-6   687CORE-14 R-4 WD-7   688 CORE-14 R-4 WD-8   689 CORE-14 R-4 WD-9   690CORE-14 R-4 WD-10  691 CORE-14 R-5 WD-1   692 CORE-14 R-5 WD-2   693CORE-14 R-5 WD-3   694 CORE-14 R-5 WD-4   695 CORE-14 R-5 WD-5   696CORE-14 R-5 WD-6   697 CORE-14 R-5 WD-7   698 CORE-14 R-5 WD-8   699CORE-14 R-5 WD-9   700 CORE-14 R-5 WD-10  701 CORE-15 R-1 WD-1   702CORE-15 R-1 WD-2   703 CORE-15 R-1 WD-3   704 CORE-15 R-1 WD-4   705CORE-15 R-1 WD-5   706 CORE-15 R-1 WD-6   707 CORE-15 R-1 WD-7   708CORE-15 R-1 WD-8   709 CORE-15 R-1 WD-9   710 CORE-15 R-1 WD-10  711CORE-15 R-2 WD-1   712 CORE-15 R-2 WD-2   713 CORE-15 R-2 WD-3   714CORE-15 R-2 WD-4   715 CORE-15 R-2 WD-5   716 CORE-15 R-2 WD-6   717CORE-15 R-2 WD-7   718 CORE-15 R-2 WD-8   719 CORE-15 R-2 WD-9   720CORE-15 R-2 WD-10  721 CORE-15 R-3 WD-1   722 CORE-15 R-3 WD-2   723CORE-15 R-3 WD-3   724 CORE-15 R-3 WD-4   725 CORE-15 R-3 WD-5   726CORE-15 R-3 WD-6   727 CORE-15 R-3 WD-7   728 CORE-15 R-3 WD-8   729CORE-15 R-3 WD-9   730 CORE-15 R-3 WD-10  731 CORE-15 R-4 WD-1   732CORE-15 R-4 WD-2   733 CORE-15 R-4 WD-3   734 CORE-15 R-4 WD-4   735CORE-15 R-4 WD-5   736 CORE-15 R-4 WD-6   737 CORE-15 R-4 WD-7   738CORE-15 R-4 WD-8   739 CORE-15 R-4 WD-9   740 CORE-15 R-4 WD-10  741CORE-15 R-5 WD-1   742 CORE-15 R-5 WD-2   743 CORE-15 R-5 WD-3   744CORE-15 R-5 WD-4   745 CORE-15 R-5 WD-5   746 CORE-15 R-5 WD-6   747CORE-15 R-5 WD-7   748 CORE-15 R-5 WD-8   749 CORE-15 R-5 WD-9   750CORE-15 R-5 WD-10  751 CORE-16 R-1 WD-1   752 CORE-16 R-1 WD-2   753CORE-16 R-1 WD-3   754 CORE-16 R-1 WD-4   755 CORE-16 R-1 WD-5   756CORE-16 R-1 WD-6   757 CORE-16 R-1 WD-7   758 CORE-16 R-1 WD-8   759CORE-16 R-1 WD-9   760 CORE-16 R-1 WD-10  761 CORE-16 R-2 WD-1   762CORE-16 R-2 WD-2   763 CORE-16 R-2 WD-3   764 CORE-16 R-2 WD-4   765CORE-16 R-2 WD-5   766 CORE-16 R-2 WD-6   767 CORE-16 R-2 WD-7   768CORE-16 R-2 WD-8   769 CORE-16 R-2 WD-9   770 CORE-16 R-2 WD-10  771CORE-16 R-3 WD-1   772 CORE-16 R-3 WD-2   773 CORE-16 R-3 WD-3   774CORE-16 R-3 WD-4   775 CORE-16 R-3 WD-5   776 CORE-16 R-3 WD-6   777CORE-16 R-3 WD-7   778 CORE-16 R-3 WD-8   779 CORE-16 R-3 WD-9   780CORE-16 R-3 WD-10  781 CORE-16 R-4 WD-1   782 CORE-16 R-4 WD-2   783CORE-16 R-4 WD-3   784 CORE-16 R-4 WD-4   785 CORE-16 R-4 WD-5   786CORE-16 R-4 WD-6   787 CORE-16 R-4 WD-7   788 CORE-16 R-4 WD-8   789CORE-16 R-4 WD-9   790 CORE-16 R-4 WD-10  791 CORE-16 R-5 WD-1   792CORE-16 R-5 WD-2   793 CORE-16 R-5 WD-3   794 CORE-16 R-5 WD-4   795CORE-16 R-5 WD-5   796 CORE-16 R-5 WD-6   797 CORE-16 R-5 WD-7   798CORE-16 R-5 WD-8   799 CORE-16 R-5 WD-9   800 CORE-16 R-5 WD-10  801CORE-17 R-1 WD-1   802 CORE-17 R-1 WD-2   803 CORE-17 R-1 WD-3   804CORE-17 R-1 WD-4   805 CORE-17 R-1 WD-5   806 CORE-17 R-1 WD-6   807CORE-17 R-1 WD-7   808 CORE-17 R-1 WD-8   809 CORE-17 R-1 WD-9   810CORE-17 R-1 WD-10  811 CORE-17 R-2 WD-1   812 CORE-17 R-2 WD-2   813CORE-17 R-2 WD-3   814 CORE-17 R-2 WD-4   815 CORE-17 R-2 WD-5   816CORE-17 R-2 WD-6   817 CORE-17 R-2 WD-7   818 CORE-17 R-2 WD-8   819CORE-17 R-2 WD-9   820 CORE-17 R-2 WD-10  821 CORE-17 R-3 WD-1   822CORE-17 R-3 WD-2   823 CORE-17 R-3 WD-3   824 CORE-17 R-3 WD-4   825CORE-17 R-3 WD-5   826 CORE-17 R-3 WD-6   827 CORE-17 R-3 WD-7   828CORE-17 R-3 WD-8   829 CORE-17 R-3 WD-9   830 CORE-17 R-3 WD-10  831CORE-17 R-4 WD-1   832 CORE-17 R-4 WD-2   833 CORE-17 R-4 WD-3   834CORE-17 R-4 WD-4   835 CORE-17 R-4 WD-5   836 CORE-17 R-4 WD-6   837CORE-17 R-4 WD-7   838 CORE-17 R-4 WD-8   839 CORE-17 R-4 WD-9   840CORE-17 R-4 WD-10  841 CORE-17 R-5 WD-1   842 CORE-17 R-5 WD-2   843CORE-17 R-5 WD-3   844 CORE-17 R-5 WD-4   845 CORE-17 R-5 WD-5   846CORE-17 R-5 WD-6   847 CORE-17 R-5 WD-7   848 CORE-17 R-5 WD-8   849CORE-17 R-5 WD-9   850 CORE-17 R-5 WD-10  851 CORE-18 R-1 WD-1   852CORE-18 R-1 WD-2   853 CORE-18 R-1 WD-3   854 CORE-18 R-1 WD-4   855CORE-18 R-1 WD-5   856 CORE-18 R-1 WD-6   857 CORE-18 R-1 WD-7   858CORE-18 R-1 WD-8   859 CORE-18 R-1 WD-9   860 CORE-18 R-1 WD-10  861CORE-18 R-2 WD-1   862 CORE-18 R-2 WD-2   863 CORE-18 R-2 WD-3   864CORE-18 R-2 WD-4   865 CORE-18 R-2 WD-5   866 CORE-18 R-2 WD-6   867CORE-18 R-2 WD-7   868 CORE-18 R-2 WD-8   869 CORE-18 R-2 WD-9   870CORE-18 R-2 WD-10  871 CORE-18 R-3 WD-1   872 CORE-18 R-3 WD-2   873CORE-18 R-3 WD-3   874 CORE-18 R-3 WD-4   875 CORE-18 R-3 WD-5   876CORE-18 R-3 WD-6   877 CORE-18 R-3 WD-7   878 CORE-18 R-3 WD-8   879CORE-18 R-3 WD-9   880 CORE-18 R-3 WD-10  881 CORE-18 R-4 WD-1   882CORE-18 R-4 WD-2   883 CORE-18 R-4 WD-3   884 CORE-18 R-4 WD-4   885CORE-18 R-4 WD-5   886 CORE-18 R-4 WD-6   887 CORE-18 R-4 WD-7   888CORE-18 R-4 WD-8   889 CORE-18 R-4 WD-9   890 CORE-18 R-4 WD-10  891CORE-18 R-5 WD-1   892 CORE-18 R-5 WD-2   893 CORE-18 R-5 WD-3   894CORE-18 R-5 WD-4   895 CORE-18 R-5 WD-5   896 CORE-18 R-5 WD-6   897CORE-18 R-5 WD-7   898 CORE-18 R-5 WD-8   899 CORE-18 R-5 WD-9   900CORE-18 R-5 WD-10  901 CORE-19 R-1 WD-1   902 CORE-19 R-1 WD-2   903CORE-19 R-1 WD-3   904 CORE-19 R-1 WD-4   905 CORE-19 R-1 WD-5   906CORE-19 R-1 WD-6   907 CORE-19 R-1 WD-7   908 CORE-19 R-1 WD-8   909CORE-19 R-1 WD-9   910 CORE-19 R-1 WD-10  911 CORE-19 R-2 WD-1   912CORE-19 R-2 WD-2   913 CORE-19 R-2 WD-3   914 CORE-19 R-2 WD-4   915CORE-19 R-2 WD-5   916 CORE-19 R-2 WD-6   917 CORE-19 R-2 WD-7   918CORE-19 R-2 WD-8   919 CORE-19 R-2 WD-9   920 CORE-19 R-2 WD-10  921CORE-19 R-3 WD-1   922 CORE-19 R-3 WD-2   923 CORE-19 R-3 WD-3   924CORE-19 R-3 WD-4   925 CORE-19 R-3 WD-5   926 CORE-19 R-3 WD-6   927CORE-19 R-3 WD-7   928 CORE-19 R-3 WD-8   929 CORE-19 R-3 WD-9   930CORE-19 R-3 WD-10  931 CORE-19 R-4 WD-1   932 CORE-19 R-4 WD-2   933CORE-19 R-4 WD-3   934 CORE-19 R-4 WD-4   935 CORE-19 R-4 WD-5   936CORE-19 R-4 WD-6   937 CORE-19 R-4 WD-7   938 CORE-19 R-4 WD-8   939CORE-19 R-4 WD-9   940 CORE-19 R-4 WD-10  941 CORE-19 R-5 WD-1   942CORE-19 R-5 WD-2   943 CORE-19 R-5 WD-3   944 CORE-19 R-5 WD-4   945CORE-19 R-5 WD-5   946 CORE-19 R-5 WD-6   947 CORE-19 R-5 WD-7   948CORE-19 R-5 WD-8   949 CORE-19 R-5 WD-9   950 CORE-19 R-5 WD-10  951CORE-20 R-1 WD-1   952 CORE-20 R-1 WD-2   953 CORE-20 R-1 WD-3   954CORE-20 R-1 WD-4   955 CORE-20 R-1 WD-5   956 CORE-20 R-1 WD-6   957CORE-20 R-1 WD-7   958 CORE-20 R-1 WD-8   959 CORE-20 R-1 WD-9   960CORE-20 R-1 WD-10  961 CORE-20 R-2 WD-1   962 CORE-20 R-2 WD-2   963CORE-20 R-2 WD-3   964 CORE-20 R-2 WD-4   965 CORE-20 R-2 WD-5   966CORE-20 R-2 WD-6   967 CORE-20 R-2 WD-7   968 CORE-20 R-2 WD-8   969CORE-20 R-2 WD-9   970 CORE-20 R-2 WD-10  971 CORE-20 R-3 WD-1   972CORE-20 R-3 WD-2   973 CORE-20 R-3 WD-3   974 CORE-20 R-3 WD-4   975CORE-20 R-3 WD-5   976 CORE-20 R-3 WD-6   977 CORE-20 R-3 WD-7   978CORE-20 R-3 WD-8   979 CORE-20 R-3 WD-9   980 CORE-20 R-3 WD-10  981CORE-20 R-4 WD-1   982 CORE-20 R-4 WD-2   983 CORE-20 R-4 WD-3   984CORE-20 R-4 WD-4   985 CORE-20 R-4 WD-5   986 CORE-20 R-4 WD-6   987CORE-20 R-4 WD-7   988 CORE-20 R-4 WD-8   989 CORE-20 R-4 WD-9   990CORE-20 R-4 WD-10  991 CORE-20 R-5 WD-1   992 CORE-20 R-5 WD-2   993CORE-20 R-5 WD-3   994 CORE-20 R-5 WD-4   995 CORE-20 R-5 WD-5   996CORE-20 R-5 WD-6   997 CORE-20 R-5 WD-7   998 CORE-20 R-5 WD-8   999CORE-20 R-5 WD-9  1000 CORE-20 R-5 WD-10 1001 CORE-21 R-1 WD-1  1002CORE-21 R-1 WD-2  1003 CORE-21 R-1 WD-3  1004 CORE-21 R-1 WD-4  1005CORE-21 R-1 WD-5  1006 CORE-21 R-1 WD-6  1007 CORE-21 R-1 WD-7  1008CORE-21 R-1 WD-8  1009 CORE-21 R-1 WD-9  1010 CORE-21 R-1 WD-10 1011CORE-21 R-2 WD-1  1012 CORE-21 R-2 WD-2  1013 CORE-21 R-2 WD-3  1014CORE-21 R-2 WD-4  1015 CORE-21 R-2 WD-5  1016 CORE-21 R-2 WD-6  1017CORE-21 R-2 WD-7  1018 CORE-21 R-2 WD-8  1019 CORE-21 R-2 WD-9  1020CORE-21 R-2 WD-10 1021 CORE-21 R-3 WD-1  1022 CORE-21 R-3 WD-2  1023CORE-21 R-3 WD-3  1024 CORE-21 R-3 WD-4  1025 CORE-21 R-3 WD-5  1026CORE-21 R-3 WD-6  1027 CORE-21 R-3 WD-7  1028 CORE-21 R-3 WD-8  1029CORE-21 R-3 WD-9  1030 CORE-21 R-3 WD-10 1031 CORE-21 R-4 WD-1  1032CORE-21 R-4 WD-2  1033 CORE-21 R-4 WD-3  1034 CORE-21 R-4 WD-4  1035CORE-21 R-4 WD-5  1036 CORE-21 R-4 WD-6  1037 CORE-21 R-4 WD-7  1038CORE-21 R-4 WD-8  1039 CORE-21 R-4 WD-9  1040 CORE-21 R-4 WD-10 1041CORE-21 R-5 WD-1  1042 CORE-21 R-5 WD-2  1043 CORE-21 R-5 WD-3  1044CORE-21 R-5 WD-4  1045 CORE-21 R-5 WD-5  1046 CORE-21 R-5 WD-6  1047CORE-21 R-5 WD-7  1048 CORE-21 R-5 WD-8  1049 CORE-21 R-5 WD-9  1050CORE-21 R-5 WD-10 1051 CORE-22 R-1 WD-1  1052 CORE-22 R-1 WD-2  1053CORE-22 R-1 WD-3  1054 CORE-22 R-1 WD-4  1055 CORE-22 R-1 WD-5  1056CORE-22 R-1 WD-6  1057 CORE-22 R-1 WD-7  1058 CORE-22 R-1 WD-8  1059CORE-22 R-1 WD-9  1060 CORE-22 R-1 WD-10 1061 CORE-22 R-2 WD-1  1062CORE-22 R-2 WD-2  1063 CORE-22 R-2 WD-3  1064 CORE-22 R-2 WD-4  1065CORE-22 R-2 WD-5  1066 CORE-22 R-2 WD-6  1067 CORE-22 R-2 WD-7  1068CORE-22 R-2 WD-8  1069 CORE-22 R-2 WD-9  1070 CORE-22 R-2 WD-10 1071CORE-22 R-3 WD-1  1072 CORE-22 R-3 WD-2  1073 CORE-22 R-3 WD-3  1074CORE-22 R-3 WD-4  1075 CORE-22 R-3 WD-5  1076 CORE-22 R-3 WD-6  1077CORE-22 R-3 WD-7  1078 CORE-22 R-3 WD-8  1079 CORE-22 R-3 WD-9  1080CORE-22 R-3 WD-10 1081 CORE-22 R-4 WD-1  1082 CORE-22 R-4 WD-2  1083CORE-22 R-4 WD-3  1084 CORE-22 R-4 WD-4  1085 CORE-22 R-4 WD-5  1086CORE-22 R-4 WD-6  1087 CORE-22 R-4 WD-7  1088 CORE-22 R-4 WD-8  1089CORE-22 R-4 WD-9  1090 CORE-22 R-4 WD-10 1091 CORE-22 R-5 WD-1  1092CORE-22 R-5 WD-2  1093 CORE-22 R-5 WD-3  1094 CORE-22 R-5 WD-4  1095CORE-22 R-5 WD-5  1096 CORE-22 R-5 WD-6  1097 CORE-22 R-5 WD-7  1098CORE-22 R-5 WD-8  1099 CORE-22 R-5 WD-9  1100 CORE-22 R-5 WD-10 1101CORE-23 R-1 WD-1  1102 CORE-23 R-1 WD-2  1103 CORE-23 R-1 WD-3  1104CORE-23 R-1 WD-4  1105 CORE-23 R-1 WD-5  1106 CORE-23 R-1 WD-6  1107CORE-23 R-1 WD-7  1108 CORE-23 R-1 WD-8  1109 CORE-23 R-1 WD-9  1110CORE-23 R-1 WD-10 1111 CORE-23 R-2 WD-1  1112 CORE-23 R-2 WD-2  1113CORE-23 R-2 WD-3  1114 CORE-23 R-2 WD-4  1115 CORE-23 R-2 WD-5  1116CORE-23 R-2 WD-6  1117 CORE-23 R-2 WD-7  1118 CORE-23 R-2 WD-8  1119CORE-23 R-2 WD-9  1120 CORE-23 R-2 WD-10 1121 CORE-23 R-3 WD-1  1122CORE-23 R-3 WD-2  1123 CORE-23 R-3 WD-3  1124 CORE-23 R-3 WD-4  1125CORE-23 R-3 WD-5  1126 CORE-23 R-3 WD-6  1127 CORE-23 R-3 WD-7  1128CORE-23 R-3 WD-8  1129 CORE-23 R-3 WD-9  1130 CORE-23 R-3 WD-10 1131CORE-23 R-4 WD-1  1132 CORE-23 R-4 WD-2  1133 CORE-23 R-4 WD-3  1134CORE-23 R-4 WD-4  1135 CORE-23 R-4 WD-5  1136 CORE-23 R-4 WD-6  1137CORE-23 R-4 WD-7  1138 CORE-23 R-4 WD-8  1139 CORE-23 R-4 WD-9  1140CORE-23 R-4 WD-10 1141 CORE-23 R-5 WD-1  1142 CORE-23 R-5 WD-2  1143CORE-23 R-5 WD-3  1144 CORE-23 R-5 WD-4  1145 CORE-23 R-5 WD-5  1146CORE-23 R-5 WD-6  1147 CORE-23 R-5 WD-7  1148 CORE-23 R-5 WD-8  1149CORE-23 R-5 WD-9  1150 CORE-23 R-5 WD-10 1151 CORE-24 R-1 WD-1  1152CORE-24 R-1 WD-2  1153 CORE-24 R-1 WD-3  1154 CORE-24 R-1 WD-4  1155CORE-24 R-1 WD-5  1156 CORE-24 R-1 WD-6  1157 CORE-24 R-1 WD-7  1158CORE-24 R-1 WD-8  1159 CORE-24 R-1 WD-9  1160 CORE-24 R-1 WD-10 1161CORE-24 R-2 WD-1  1162 CORE-24 R-2 WD-2  1163 CORE-24 R-2 WD-3  1164CORE-24 R-2 WD-4  1165 CORE-24 R-2 WD-5  1166 CORE-24 R-2 WD-6  1167CORE-24 R-2 WD-7  1168 CORE-24 R-2 WD-8  1169 CORE-24 R-2 WD-9  1170CORE-24 R-2 WD-10 1171 CORE-24 R-3 WD-1  1172 CORE-24 R-3 WD-2  1173CORE-24 R-3 WD-3  1174 CORE-24 R-3 WD-4  1175 CORE-24 R-3 WD-5  1176CORE-24 R-3 WD-6  1177 CORE-24 R-3 WD-7  1178 CORE-24 R-3 WD-8  1179CORE-24 R-3 WD-9  1180 CORE-24 R-3 WD-10 1181 CORE-24 R-4 WD-1  1182CORE-24 R-4 WD-2  1183 CORE-24 R-4 WD-3  1184 CORE-24 R-4 WD-4  1185CORE-24 R-4 WD-5  1186 CORE-24 R-4 WD-6  1187 CORE-24 R-4 WD-7  1188CORE-24 R-4 WD-8  1189 CORE-24 R-4 WD-9  1190 CORE-24 R-4 WD-10 1191CORE-24 R-5 WD-1  1192 CORE-24 R-5 WD-2  1193 CORE-24 R-5 WD-3  1194CORE-24 R-5 WD-4  1195 CORE-24 R-5 WD-5  1196 CORE-24 R-5 WD-6  1197CORE-24 R-5 WD-7  1198 CORE-24 R-5 WD-8  1199 CORE-24 R-5 WD-9  1200CORE-24 R-5 WD-10 1201 CORE-25 R-1 WD-1  1202 CORE-25 R-1 WD-2  1203CORE-25 R-1 WD-3  1204 CORE-25 R-1 WD-4  1205 CORE-25 R-1 WD-5  1206CORE-25 R-1 WD-6  1207 CORE-25 R-1 WD-7  1208 CORE-25 R-1 WD-8  1209CORE-25 R-1 WD-9  1210 CORE-25 R-1 WD-10 1211 CORE-25 R-2 WD-1  1212CORE-25 R-2 WD-2  1213 CORE-25 R-2 WD-3  1214 CORE-25 R-2 WD-4  1215CORE-25 R-2 WD-5  1216 CORE-25 R-2 WD-6  1217 CORE-25 R-2 WD-7  1218CORE-25 R-2 WD-8  1219 CORE-25 R-2 WD-9  1220 CORE-25 R-2 WD-10 1221CORE-25 R-3 WD-1  1222 CORE-25 R-3 WD-2  1223 CORE-25 R-3 WD-3  1224CORE-25 R-3 WD-4  1225 CORE-25 R-3 WD-5  1226 CORE-25 R-3 WD-6  1227CORE-25 R-3 WD-7  1228 CORE-25 R-3 WD-8  1229 CORE-25 R-3 WD-9  1230CORE-25 R-3 WD-10 1231 CORE-25 R-4 WD-1  1232 CORE-25 R-4 WD-2  1233CORE-25 R-4 WD-3  1234 CORE-25 R-4 WD-4  1235 CORE-25 R-4 WD-5  1236CORE-25 R-4 WD-6  1237 CORE-25 R-4 WD-7  1238 CORE-25 R-4 WD-8  1239CORE-25 R-4 WD-9  1240 CORE-25 R-4 WD-10 1241 CORE-25 R-5 WD-1  1242CORE-25 R-5 WD-2  1243 CORE-25 R-5 WD-3  1244 CORE-25 R-5 WD-4  1245CORE-25 R-5 WD-5  1246 CORE-25 R-5 WD-6  1247 CORE-25 R-5 WD-7  1248CORE-25 R-5 WD-8  1249 CORE-25 R-5 WD-9  1250 CORE-25 R-5 WD-10 1251CORE-26 R-1 WD-1  1252 CORE-26 R-1 WD-2  1253 CORE-26 R-1 WD-3  1254CORE-26 R-1 WD-4  1255 CORE-26 R-1 WD-5  1256 CORE-26 R-1 WD-6  1257CORE-26 R-1 WD-7  1258 CORE-26 R-1 WD-8  1259 CORE-26 R-1 WD-9  1260CORE-26 R-1 WD-10 1261 CORE-26 R-2 WD-1  1262 CORE-26 R-2 WD-2  1263CORE-26 R-2 WD-3  1264 CORE-26 R-2 WD-4  1265 CORE-26 R-2 WD-5  1266CORE-26 R-2 WD-6  1267 CORE-26 R-2 WD-7  1268 CORE-26 R-2 WD-8  1269CORE-26 R-2 WD-9  1270 CORE-26 R-2 WD-10 1271 CORE-26 R-3 WD-1  1272CORE-26 R-3 WD-2  1273 CORE-26 R-3 WD-3  1274 CORE-26 R-3 WD-4  1275CORE-26 R-3 WD-5  1276 CORE-26 R-3 WD-6  1277 CORE-26 R-3 WD-7  1278CORE-26 R-3 WD-8  1279 CORE-26 R-3 WD-9  1280 CORE-26 R-3 WD-10 1281CORE-26 R-4 WD-1  1282 CORE-26 R-4 WD-2  1283 CORE-26 R-4 WD-3  1284CORE-26 R-4 WD-4  1285 CORE-26 R-4 WD-5  1286 CORE-26 R-4 WD-6  1287CORE-26 R-4 WD-7  1288 CORE-26 R-4 WD-8  1289 CORE-26 R-4 WD-9  1290CORE-26 R-4 WD-10 1291 CORE-26 R-5 WD-1  1292 CORE-26 R-5 WD-2  1293CORE-26 R-5 WD-3  1294 CORE-26 R-5 WD-4  1295 CORE-26 R-5 WD-5  1296CORE-26 R-5 WD-6  1297 CORE-26 R-5 WD-7  1298 CORE-26 R-5 WD-8  1299CORE-26 R-5 WD-9  1300 CORE-26 R-5 WD-10 1301 CORE-27 R-1 WD-1  1302CORE-27 R-1 WD-2  1303 CORE-27 R-1 WD-3  1304 CORE-27 R-1 WD-4  1305CORE-27 R-1 WD-5  1306 CORE-27 R-1 WD-6  1307 CORE-27 R-1 WD-7  1308CORE-27 R-1 WD-8  1309 CORE-27 R-1 WD-9  1310 CORE-27 R-1 WD-10 1311CORE-27 R-2 WD-1  1312 CORE-27 R-2 WD-2  1313 CORE-27 R-2 WD-3  1314CORE-27 R-2 WD-4  1315 CORE-27 R-2 WD-5  1316 CORE-27 R-2 WD-6  1317CORE-27 R-2 WD-7  1318 CORE-27 R-2 WD-8  1319 CORE-27 R-2 WD-9  1320CORE-27 R-2 WD-10 1321 CORE-27 R-3 WD-1  1322 CORE-27 R-3 WD-2  1323CORE-27 R-3 WD-3  1324 CORE-27 R-3 WD-4  1325 CORE-27 R-3 WD-5  1326CORE-27 R-3 WD-6  1327 CORE-27 R-3 WD-7  1328 CORE-27 R-3 WD-8  1329CORE-27 R-3 WD-9  1330 CORE-27 R-3 WD-10 1331 CORE-27 R-4 WD-1  1332CORE-27 R-4 WD-2  1333 CORE-27 R-4 WD-3  1334 CORE-27 R-4 WD-4  1335CORE-27 R-4 WD-5  1336 CORE-27 R-4 WD-6  1337 CORE-27 R-4 WD-7  1338CORE-27 R-4 WD-8  1339 CORE-27 R-4 WD-9  1340 CORE-27 R-4 WD-10 1341CORE-27 R-5 WD-1  1342 CORE-27 R-5 WD-2  1343 CORE-27 R-5 WD-3  1344CORE-27 R-5 WD-4  1345 CORE-27 R-5 WD-5  1346 CORE-27 R-5 WD-6  1347CORE-27 R-5 WD-7  1348 CORE-27 R-5 WD-8  1349 CORE-27 R-5 WD-9  1350CORE-27 R-5 WD-10 1351 CORE-28 R-1 WD-1  1352 CORE-28 R-1 WD-2  1353CORE-28 R-1 WD-3  1354 CORE-28 R-1 WD-4  1355 CORE-28 R-1 WD-5  1356CORE-28 R-1 WD-6  1357 CORE-28 R-1 WD-7  1358 CORE-28 R-1 WD-8  1359CORE-28 R-1 WD-9  1360 CORE-28 R-1 WD-10 1361 CORE-28 R-2 WD-1  1362CORE-28 R-2 WD-2  1363 CORE-28 R-2 WD-3  1364 CORE-28 R-2 WD-4  1365CORE-28 R-2 WD-5  1366 CORE-28 R-2 WD-6  1367 CORE-28 R-2 WD-7  1368CORE-28 R-2 WD-8  1369 CORE-28 R-2 WD-9  1370 CORE-28 R-2 WD-10 1371CORE-28 R-3 WD-1  1372 CORE-28 R-3 WD-2  1373 CORE-28 R-3 WD-3  1374CORE-28 R-3 WD-4  1375 CORE-28 R-3 WD-5  1376 CORE-28 R-3 WD-6  1377CORE-28 R-3 WD-7  1378 CORE-28 R-3 WD-8  1379 CORE-28 R-3 WD-9  1380CORE-28 R-3 WD-10 1381 CORE-28 R-4 WD-1  1382 CORE-28 R-4 WD-2  1383CORE-28 R-4 WD-3  1384 CORE-28 R-4 WD-4  1385 CORE-28 R-4 WD-5  1386CORE-28 R-4 WD-6  1387 CORE-28 R-4 WD-7  1388 CORE-28 R-4 WD-8  1389CORE-28 R-4 WD-9  1390 CORE-28 R-4 WD-10 1391 CORE-28 R-5 WD-1  1392CORE-28 R-5 WD-2  1393 CORE-28 R-5 WD-3  1394 CORE-28 R-5 WD-4  1395CORE-28 R-5 WD-5  1396 CORE-28 R-5 WD-6  1397 CORE-28 R-5 WD-7  1398CORE-28 R-5 WD-8  1399 CORE-28 R-5 WD-9  1400 CORE-28 R-5 WD-10 1401CORE-29 R-1 WD-1  1402 CORE-29 R-1 WD-2  1403 CORE-29 R-1 WD-3  1404CORE-29 R-1 WD-4  1405 CORE-29 R-1 WD-5  1406 CORE-29 R-1 WD-6  1407CORE-29 R-1 WD-7  1408 CORE-29 R-1 WD-8  1409 CORE-29 R-1 WD-9  1410CORE-29 R-1 WD-10 1411 CORE-29 R-2 WD-1  1412 CORE-29 R-2 WD-2  1413CORE-29 R-2 WD-3  1414 CORE-29 R-2 WD-4  1415 CORE-29 R-2 WD-5  1416CORE-29 R-2 WD-6  1417 CORE-29 R-2 WD-7  1418 CORE-29 R-2 WD-8  1419CORE-29 R-2 WD-9  1420 CORE-29 R-2 WD-10 1421 CORE-29 R-3 WD-1  1422CORE-29 R-3 WD-2  1423 CORE-29 R-3 WD-3  1424 CORE-29 R-3 WD-4  1425CORE-29 R-3 WD-5  1426 CORE-29 R-3 WD-6  1427 CORE-29 R-3 WD-7  1428CORE-29 R-3 WD-8  1429 CORE-29 R-3 WD-9  1430 CORE-29 R-3 WD-10 1431CORE-29 R-4 WD-1  1432 CORE-29 R-4 WD-2  1433 CORE-29 R-4 WD-3  1434CORE-29 R-4 WD-4  1435 CORE-29 R-4 WD-5  1436 CORE-29 R-4 WD-6  1437CORE-29 R-4 WD-7  1438 CORE-29 R-4 WD-8  1439 CORE-29 R-4 WD-9  1440CORE-29 R-4 WD-10 1441 CORE-29 R-5 WD-1  1442 CORE-29 R-5 WD-2  1443CORE-29 R-5 WD-3  1444 CORE-29 R-5 WD-4  1445 CORE-29 R-5 WD-5  1446CORE-29 R-5 WD-6  1447 CORE-29 R-5 WD-7  1448 CORE-29 R-5 WD-8  1449CORE-29 R-5 WD-9  1450 CORE-29 R-5 WD-10 1451 CORE-1  R-1 WD-11 1452CORE-1  R-1 WD-12 1453 CORE-1  R-1 WD-13 1454 CORE-1  R-1 WD-14 1455CORE-1  R-1 WD-15 1456 CORE-1  R-1 WD-16 1457 CORE-1  R-1 WD-17 1458CORE-1  R-1 WD-18 1459 CORE-1  R-1 WD-19 1460 CORE-1  R-1 WD-20 1461CORE-1  R-1 WD-21 1462 CORE-1  R-1 WD-22 1463 CORE-1  R-1 WD-23 1464CORE-1  R-1 WD-24 1465 CORE-1  R-1 WD-25 1466 CORE-1  R-2 WD-11 1467CORE-1  R-2 WD-12 1468 CORE-1  R-2 WD-13 1469 CORE-1  R-2 WD-14 1470CORE-1  R-2 WD-15 1471 CORE-1  R-2 WD-16 1472 CORE-1  R-2 WD-17 1473CORE-1  R-2 WD-18 1474 CORE-1  R-2 WD-19 1475 CORE-1  R-2 WD-20 1476CORE-1  R-2 WD-21 1477 CORE-1  R-2 WD-22 1478 CORE-1  R-2 WD-23 1479CORE-1  R-2 WD-24 1480 CORE-1  R-2 WD-25 1481 CORE-1  R-3 WD-11 1482CORE-1  R-3 WD-12 1483 CORE-1  R-3 WD-13 1484 CORE-1  R-3 WD-14 1485CORE-1  R-3 WD-15 1486 CORE-1  R-3 WD-16 1487 CORE-1  R-3 WD-17 1488CORE-1  R-3 WD-18 1489 CORE-1  R-3 WD-19 1490 CORE-1  R-3 WD-20 1491CORE-1  R-3 WD-21 1492 CORE-1  R-3 WD-22 1493 CORE-1  R-3 WD-23 1494CORE-1  R-3 WD-24 1495 CORE-1  R-3 WD-25 1496 CORE-1  R-4 WD-11 1497CORE-1  R-4 WD-12 1498 CORE-1  R-4 WD-13 1499 CORE-1  R-4 WD-14 1500CORE-1  R-4 WD-15 1501 CORE-1  R-4 WD-16 1502 CORE-1  R-4 WD-17 1503CORE-1  R-4 WD-18 1504 CORE-1  R-4 WD-19 1505 CORE-1  R-4 WD-20 1506CORE-1  R-4 WD-21 1507 CORE-1  R-4 WD-22 1508 CORE-1  R-4 WD-23 1509CORE-1  R-4 WD-24 1510 CORE-1  R-4 WD-25 1511 CORE-1  R-5 WD-11 1512CORE-1  R-5 WD-12 1513 CORE-1  R-5 WD-13 1514 CORE-1  R-5 WD-14 1515CORE-1  R-5 WD-15 1516 CORE-1  R-5 WD-16 1517 CORE-1  R-5 WD-17 1518CORE-1  R-5 WD-18 1519 CORE-1  R-5 WD-19 1520 CORE-1  R-5 WD-20 1521CORE-1  R-5 WD-21 1522 CORE-1  R-5 WD-22 1523 CORE-1  R-5 WD-23 1524CORE-1  R-5 WD-24 1525 CORE-1  R-5 WD-25 1526 CORE-2  R-1 WD-11 1527CORE-2  R-1 WD-12 1528 CORE-2  R-1 WD-13 1529 CORE-2  R-1 WD-14 1530CORE-2  R-1 WD-15 1531 CORE-2  R-1 WD-16 1532 CORE-2  R-1 WD-17 1533CORE-2  R-1 WD-18 1534 CORE-2  R-1 WD-19 1535 CORE-2  R-1 WD-20 1536CORE-2  R-1 WD-21 1537 CORE-2  R-1 WD-22 1538 CORE-2  R-1 WD-23 1539CORE-2  R-1 WD-24 1540 CORE-2  R-1 WD-25 1541 CORE-2  R-2 WD-11 1542CORE-2  R-2 WD-12 1543 CORE-2  R-2 WD-13 1544 CORE-2  R-2 WD-14 1545CORE-2  R-2 WD-15 1546 CORE-2  R-2 WD-16 1547 CORE-2  R-2 WD-17 1548CORE-2  R-2 WD-18 1549 CORE-2  R-2 WD-19 1550 CORE-2  R-2 WD-20 1551CORE-2  R-2 WD-21 1552 CORE-2  R-2 WD-22 1553 CORE-2  R-2 WD-23 1554CORE-2  R-2 WD-24 1555 CORE-2  R-2 WD-25 1556 CORE-2  R-3 WD-11 1557CORE-2  R-3 WD-12 1558 CORE-2  R-3 WD-13 1559 CORE-2  R-3 WD-14 1560CORE-2  R-3 WD-15 1561 CORE-2  R-3 WD-16 1562 CORE-2  R-3 WD-17 1563CORE-2  R-3 WD-18 1564 CORE-2  R-3 WD-19 1565 CORE-2  R-3 WD-20 1566CORE-2  R-3 WD-21 1567 CORE-2  R-3 WD-22 1568 CORE-2  R-3 WD-23 1569CORE-2  R-3 WD-24 1570 CORE-2  R-3 WD-25 1571 CORE-2  R-4 WD-11 1572CORE-2  R-4 WD-12 1573 CORE-2  R-4 WD-13 1574 CORE-2  R-4 WD-14 1575CORE-2  R-4 WD-15 1576 CORE-2  R-4 WD-16 1577 CORE-2  R-4 WD-17 1578CORE-2  R-4 WD-18 1579 CORE-2  R-4 WD-19 1580 CORE-2  R-4 WD-20 1581CORE-2  R-4 WD-21 1582 CORE-2  R-4 WD-22 1583 CORE-2  R-4 WD-23 1584CORE-2  R-4 WD-24 1585 CORE-2  R-4 WD-25 1586 CORE-2  R-5 WD-11 1587CORE-2  R-5 WD-12 1588 CORE-2  R-5 WD-13 1589 CORE-2  R-5 WD-14 1590CORE-2  R-5 WD-15 1591 CORE-2  R-5 WD-16 1592 CORE-2  R-5 WD-17 1593CORE-2  R-5 WD-18 1594 CORE-2  R-5 WD-19 1595 CORE-2  R-5 WD-20 1596CORE-2  R-5 WD-21 1597 CORE-2  R-5 WD-22 1598 CORE-2  R-5 WD-23 1599CORE-2  R-5 WD-24 1600 CORE-2  R-5 WD-25 1601 CORE-3  R-1 WD-11 1602CORE-3  R-1 WD-12 1603 CORE-3  R-1 WD-13 1604 CORE-3  R-1 WD-14 1605CORE-3  R-1 WD-15 1606 CORE-3  R-1 WD-16 1607 CORE-3  R-1 WD-17 1608CORE-3  R-1 WD-18 1609 CORE-3  R-1 WD-19 1610 CORE-3  R-1 WD-20 1611CORE-3  R-1 WD-21 1612 CORE-3  R-1 WD-22 1613 CORE-3  R-1 WD-23 1614CORE-3  R-1 WD-24 1615 CORE-3  R-1 WD-25 1616 CORE-3  R-2 WD-11 1617CORE-3  R-2 WD-12 1618 CORE-3  R-2 WD-13 1619 CORE-3  R-2 WD-14 1620CORE-3  R-2 WD-15 1621 CORE-3  R-2 WD-16 1622 CORE-3  R-2 WD-17 1623CORE-3  R-2 WD-18 1624 CORE-3  R-2 WD-19 1625 CORE-3  R-2 WD-20 1626CORE-3  R-2 WD-21 1627 CORE-3  R-2 WD-22 1628 CORE-3  R-2 WD-23 1629CORE-3  R-2 WD-24 1630 CORE-3  R-2 WD-25 1631 CORE-3  R-3 WD-11 1632CORE-3  R-3 WD-12 1633 CORE-3  R-3 WD-13 1634 CORE-3  R-3 WD-14 1635CORE-3  R-3 WD-15 1636 CORE-3  R-3 WD-16 1637 CORE-3  R-3 WD-17 1638CORE-3  R-3 WD-18 1639 CORE-3  R-3 WD-19 1640 CORE-3  R-3 WD-20 1641CORE-3  R-3 WD-21 1642 CORE-3  R-3 WD-22 1643 CORE-3  R-3 WD-23 1644CORE-3  R-3 WD-24 1645 CORE-3  R-3 WD-25 1646 CORE-3  R-4 WD-11 1647CORE-3  R-4 WD-12 1648 CORE-3  R-4 WD-13 1649 CORE-3  R-4 WD-14 1650CORE-3  R-4 WD-15 1651 CORE-3  R-4 WD-16 1652 CORE-3  R-4 WD-17 1653CORE-3  R-4 WD-18 1654 CORE-3  R-4 WD-19 1655 CORE-3  R-4 WD-20 1656CORE-3  R-4 WD-21 1657 CORE-3  R-4 WD-22 1658 CORE-3  R-4 WD-23 1659CORE-3  R-4 WD-24 1660 CORE-3  R-4 WD-25 1661 CORE-3  R-5 WD-11 1662CORE-3  R-5 WD-12 1663 CORE-3  R-5 WD-13 1664 CORE-3  R-5 WD-14 1665CORE-3  R-5 WD-15 1666 CORE-3  R-5 WD-16 1667 CORE-3  R-5 WD-17 1668CORE-3  R-5 WD-18 1669 CORE-3  R-5 WD-19 1670 CORE-3  R-5 WD-20 1671CORE-3  R-5 WD-21 1672 CORE-3  R-5 WD-22 1673 CORE-3  R-5 WD-23 1674CORE-3  R-5 WD-24 1675 CORE-3  R-5 WD-25 1676 CORE-4  R-1 WD-11 1677CORE-4  R-1 WD-12 1678 CORE-4  R-1 WD-13 1679 CORE-4  R-1 WD-14 1680CORE-4  R-1 WD-15 1681 CORE-4  R-1 WD-16 1682 CORE-4  R-1 WD-17 1683CORE-4  R-1 WD-18 1684 CORE-4  R-1 WD-19 1685 CORE-4  R-1 WD-20 1686CORE-4  R-1 WD-21 1687 CORE-4  R-1 WD-22 1688 CORE-4  R-1 WD-23 1689CORE-4  R-1 WD-24 1690 CORE-4  R-1 WD-25 1691 CORE-4  R-2 WD-11 1692CORE-4  R-2 WD-12 1693 CORE-4  R-2 WD-13 1694 CORE-4  R-2 WD-14 1695CORE-4  R-2 WD-15 1696 CORE-4  R-2 WD-16 1697 CORE-4  R-2 WD-17 1698CORE-4  R-2 WD-18 1699 CORE-4  R-2 WD-19 1700 CORE-4  R-2 WD-20 1701CORE-4  R-2 WD-21 1702 CORE-4  R-2 WD-22 1703 CORE-4  R-2 WD-23 1704CORE-4  R-2 WD-24 1705 CORE-4  R-2 WD-25 1706 CORE-4  R-3 WD-11 1707CORE-4  R-3 WD-12 1708 CORE-4  R-3 WD-13 1709 CORE-4  R-3 WD-14 1710CORE-4  R-3 WD-15 1711 CORE-4  R-3 WD-16 1712 CORE-4  R-3 WD-17 1713CORE-4  R-3 WD-18 1714 CORE-4  R-3 WD-19 1715 CORE-4  R-3 WD-20 1716CORE-4  R-3 WD-21 1717 CORE-4  R-3 WD-22 1718 CORE-4  R-3 WD-23 1719CORE-4  R-3 WD-24 1720 CORE-4  R-3 WD-25 1721 CORE-4  R-4 WD-11 1722CORE-4  R-4 WD-12 1723 CORE-4  R-4 WD-13 1724 CORE-4  R-4 WD-14 1725CORE-4  R-4 WD-15 1726 CORE-4  R-4 WD-16 1727 CORE-4  R-4 WD-17 1728CORE-4  R-4 WD-18 1729 CORE-4  R-4 WD-19 1730 CORE-4  R-4 WD-20 1731CORE-4  R-4 WD-21 1732 CORE-4  R-4 WD-22 1733 CORE-4  R-4 WD-23 1734CORE-4  R-4 WD-24 1735 CORE-4  R-4 WD-25 1736 CORE-4  R-5 WD-11 1737CORE-4  R-5 WD-12 1738 CORE-4  R-5 WD-13 1739 CORE-4  R-5 WD-14 1740CORE-4  R-5 WD-15 1741 CORE-4  R-5 WD-16 1742 CORE-4  R-5 WD-17 1743CORE-4  R-5 WD-18 1744 CORE-4  R-5 WD-19 1745 CORE-4  R-5 WD-20 1746CORE-4  R-5 WD-21 1747 CORE-4  R-5 WD-22 1748 CORE-4  R-5 WD-23 1749CORE-4  R-5 WD-24 1750 CORE-4  R-5 WD-25 1751 CORE-5  R-1 WD-11 1752CORE-5  R-1 WD-12 1753 CORE-5  R-1 WD-13 1754 CORE-5  R-1 WD-14 1755CORE-5  R-1 WD-15 1756 CORE-5  R-1 WD-16 1757 CORE-5  R-1 WD-17 1758CORE-5  R-1 WD-18 1759 CORE-5  R-1 WD-19 1760 CORE-5  R-1 WD-20 1761CORE-5  R-1 WD-21 1762 CORE-5  R-1 WD-22 1763 CORE-5  R-1 WD-23 1764CORE-5  R-1 WD-24 1765 CORE-5  R-1 WD-25 1766 CORE-5  R-2 WD-11 1767CORE-5  R-2 WD-12 1768 CORE-5  R-2 WD-13 1769 CORE-5  R-2 WD-14 1770CORE-5  R-2 WD-15 1771 CORE-5  R-2 WD-16 1772 CORE-5  R-2 WD-17 1773CORE-5  R-2 WD-18 1774 CORE-5  R-2 WD-19 1775 CORE-5  R-2 WD-20 1776CORE-5  R-2 WD-21 1777 CORE-5  R-2 WD-22 1778 CORE-5  R-2 WD-23 1779CORE-5  R-2 WD-24 1780 CORE-5  R-2 WD-25 1781 CORE-5  R-3 WD-11 1782CORE-5  R-3 WD-12 1783 CORE-5  R-3 WD-13 1784 CORE-5  R-3 WD-14 1785CORE-5  R-3 WD-15 1786 CORE-5  R-3 WD-16 1787 CORE-5  R-3 WD-17 1788CORE-5  R-3 WD-18 1789 CORE-5  R-3 WD-19 1790 CORE-5  R-3 WD-20 1791CORE-5  R-3 WD-21 1792 CORE-5  R-3 WD-22 1793 CORE-5  R-3 WD-23 1794CORE-5  R-3 WD-24 1795 CORE-5  R-3 WD-25 1796 CORE-5  R-4 WD-11 1797CORE-5  R-4 WD-12 1798 CORE-5  R-4 WD-13 1799 CORE-5  R-4 WD-14 1800CORE-5  R-4 WD-15 1801 CORE-5  R-4 WD-16 1802 CORE-5  R-4 WD-17 1803CORE-5  R-4 WD-18 1804 CORE-5  R-4 WD-19 1805 CORE-5  R-4 WD-20 1806CORE-5  R-4 WD-21 1807 CORE-5  R-4 WD-22 1808 CORE-5  R-4 WD-23 1809CORE-5  R-4 WD-24 1810 CORE-5  R-4 WD-25 1811 CORE-5  R-5 WD-11 1812CORE-5  R-5 WD-12 1813 CORE-5  R-5 WD-13 1814 CORE-5  R-5 WD-14 1815CORE-5  R-5 WD-15 1816 CORE-5  R-5 WD-16 1817 CORE-5  R-5 WD-17 1818CORE-5  R-5 WD-18 1819 CORE-5  R-5 WD-19 1820 CORE-5  R-5 WD-20 1821CORE-5  R-5 WD-21 1822 CORE-5  R-5 WD-22 1823 CORE-5  R-5 WD-23 1824CORE-5  R-5 WD-24 1825 CORE-5  R-5 WD-25 1826 CORE-6  R-1 WD-11 1827CORE-6  R-1 WD-12 1828 CORE-6  R-1 WD-13 1829 CORE-6  R-1 WD-14 1830CORE-6  R-1 WD-15 1831 CORE-6  R-1 WD-16 1832 CORE-6  R-1 WD-17 1833CORE-6  R-1 WD-18 1834 CORE-6  R-1 WD-19 1835 CORE-6  R-1 WD-20 1836CORE-6  R-1 WD-21 1837 CORE-6  R-1 WD-22 1838 CORE-6  R-1 WD-23 1839CORE-6  R-1 WD-24 1840 CORE-6  R-1 WD-25 1841 CORE-6  R-2 WD-11 1842CORE-6  R-2 WD-12 1843 CORE-6  R-2 WD-13 1844 CORE-6  R-2 WD-14 1845CORE-6  R-2 WD-15 1846 CORE-6  R-2 WD-16 1847 CORE-6  R-2 WD-17 1848CORE-6  R-2 WD-18 1849 CORE-6  R-2 WD-19 1850 CORE-6  R-2 WD-20 1851CORE-6  R-2 WD-21 1852 CORE-6  R-2 WD-22 1853 CORE-6  R-2 WD-23 1854CORE-6  R-2 WD-24 1855 CORE-6  R-2 WD-25 1856 CORE-6  R-3 WD-11 1857CORE-6  R-3 WD-12 1858 CORE-6  R-3 WD-13 1859 CORE-6  R-3 WD-14 1860CORE-6  R-3 WD-15 1861 CORE-6  R-3 WD-16 1862 CORE-6  R-3 WD-17 1863CORE-6  R-3 WD-18 1864 CORE-6  R-3 WD-19 1865 CORE-6  R-3 WD-20 1866CORE-6  R-3 WD-21 1867 CORE-6  R-3 WD-22 1868 CORE-6  R-3 WD-23 1869CORE-6  R-3 WD-24 1870 CORE-6  R-3 WD-25 1871 CORE-6  R-4 WD-11 1872CORE-6  R-4 WD-12 1873 CORE-6  R-4 WD-13 1874 CORE-6  R-4 WD-14 1875CORE-6  R-4 WD-15 1876 CORE-6  R-4 WD-16 1877 CORE-6  R-4 WD-17 1878CORE-6  R-4 WD-18 1879 CORE-6  R-4 WD-19 1880 CORE-6  R-4 WD-20 1881CORE-6  R-4 WD-21 1882 CORE-6  R-4 WD-22 1883 CORE-6  R-4 WD-23 1884CORE-6  R-4 WD-24 1885 CORE-6  R-4 WD-25 1886 CORE-6  R-5 WD-11 1887CORE-6  R-5 WD-12 1888 CORE-6  R-5 WD-13 1889 CORE-6  R-5 WD-14 1890CORE-6  R-5 WD-15 1891 CORE-6  R-5 WD-16 1892 CORE-6  R-5 WD-17 1893CORE-6  R-5 WD-18 1894 CORE-6  R-5 WD-19 1895 CORE-6  R-5 WD-20 1896CORE-6  R-5 WD-21 1897 CORE-6  R-5 WD-22 1898 CORE-6  R-5 WD-23 1899CORE-6  R-5 WD-24 1900 CORE-6  R-5 WD-25 1901 CORE-7  R-1 WD-11 1902CORE-7  R-1 WD-12 1903 CORE-7  R-1 WD-13 1904 CORE-7  R-1 WD-14 1905CORE-7  R-1 WD-15 1906 CORE-7  R-1 WD-16 1907 CORE-7  R-1 WD-17 1908CORE-7  R-1 WD-18 1909 CORE-7  R-1 WD-19 1910 CORE-7  R-1 WD-20 1911CORE-7  R-1 WD-21 1912 CORE-7  R-1 WD-22 1913 CORE-7  R-1 WD-23 1914CORE-7  R-1 WD-24 1915 CORE-7  R-1 WD-25 1916 CORE-7  R-2 WD-11 1917CORE-7  R-2 WD-12 1918 CORE-7  R-2 WD-13 1919 CORE-7  R-2 WD-14 1920CORE-7  R-2 WD-15 1921 CORE-7  R-2 WD-16 1922 CORE-7  R-2 WD-17 1923CORE-7  R-2 WD-18 1924 CORE-7  R-2 WD-19 1925 CORE-7  R-2 WD-20 1926CORE-7  R-2 WD-21 1927 CORE-7  R-2 WD-22 1928 CORE-7  R-2 WD-23 1929CORE-7  R-2 WD-24 1930 CORE-7  R-2 WD-25 1931 CORE-7  R-3 WD-11 1932CORE-7  R-3 WD-12 1933 CORE-7  R-3 WD-13 1934 CORE-7  R-3 WD-14 1935CORE-7  R-3 WD-15 1936 CORE-7  R-3 WD-16 1937 CORE-7  R-3 WD-17 1938CORE-7  R-3 WD-18 1939 CORE-7  R-3 WD-19 1940 CORE-7  R-3 WD-20 1941CORE-7  R-3 WD-21 1942 CORE-7  R-3 WD-22 1943 CORE-7  R-3 WD-23 1944CORE-7  R-3 WD-24 1945 CORE-7  R-3 WD-25 1946 CORE-7  R-4 WD-11 1947CORE-7  R-4 WD-12 1948 CORE-7  R-4 WD-13 1949 CORE-7  R-4 WD-14 1950CORE-7  R-4 WD-15 1951 CORE-7  R-4 WD-16 1952 CORE-7  R-4 WD-17 1953CORE-7  R-4 WD-18 1954 CORE-7  R-4 WD-19 1955 CORE-7  R-4 WD-20 1956CORE-7  R-4 WD-21 1957 CORE-7  R-4 WD-22 1958 CORE-7  R-4 WD-23 1959CORE-7  R-4 WD-24 1960 CORE-7  R-4 WD-25 1961 CORE-7  R-5 WD-11 1962CORE-7  R-5 WD-12 1963 CORE-7  R-5 WD-13 1964 CORE-7  R-5 WD-14 1965CORE-7  R-5 WD-15 1966 CORE-7  R-5 WD-16 1967 CORE-7  R-5 WD-17 1968CORE-7  R-5 WD-18 1969 CORE-7  R-5 WD-19 1970 CORE-7  R-5 WD-20 1971CORE-7  R-5 WD-21 1972 CORE-7  R-5 WD-22 1973 CORE-7  R-5 WD-23 1974CORE-7  R-5 WD-24 1975 CORE-7  R-5 WD-25 1976 CORE-8  R-1 WD-11 1977CORE-8  R-1 WD-12 1978 CORE-8  R-1 WD-13 1979 CORE-8  R-1 WD-14 1980CORE-8  R-1 WD-15 1981 CORE-8  R-1 WD-16 1982 CORE-8  R-1 WD-17 1983CORE-8  R-1 WD-18 1984 CORE-8  R-1 WD-19 1985 CORE-8  R-1 WD-20 1986CORE-8  R-1 WD-21 1987 CORE-8  R-1 WD-22 1988 CORE-8  R-1 WD-23 1989CORE-8  R-1 WD-24 1990 CORE-8  R-1 WD-25 1991 CORE-8  R-2 WD-11 1992CORE-8  R-2 WD-12 1993 CORE-8  R-2 WD-13 1994 CORE-8  R-2 WD-14 1995CORE-8  R-2 WD-15 1996 CORE-8  R-2 WD-16 1997 CORE-8  R-2 WD-17 1998CORE-8  R-2 WD-18 1999 CORE-8  R-2 WD-19 2000 CORE-8  R-2 WD-20 2001CORE-8  R-2 WD-21 2002 CORE-8  R-2 WD-22 2003 CORE-8  R-2 WD-23 2004CORE-8  R-2 WD-24 2005 CORE-8  R-2 WD-25 2006 CORE-8  R-3 WD-11 2007CORE-8  R-3 WD-12 2008 CORE-8  R-3 WD-13 2009 CORE-8  R-3 WD-14 2010CORE-8  R-3 WD-15 2011 CORE-8  R-3 WD-16 2012 CORE-8  R-3 WD-17 2013CORE-8  R-3 WD-18 2014 CORE-8  R-3 WD-19 2015 CORE-8  R-3 WD-20 2016CORE-8  R-3 WD-21 2017 CORE-8  R-3 WD-22 2018 CORE-8  R-3 WD-23 2019CORE-8  R-3 WD-24 2020 CORE-8  R-3 WD-25 2021 CORE-8  R-4 WD-11 2022CORE-8  R-4 WD-12 2023 CORE-8  R-4 WD-13 2024 CORE-8  R-4 WD-14 2025CORE-8  R-4 WD-15 2026 CORE-8  R-4 WD-16 2027 CORE-8  R-4 WD-17 2028CORE-8  R-4 WD-18 2029 CORE-8  R-4 WD-19 2030 CORE-8  R-4 WD-20 2031CORE-8  R-4 WD-21 2032 CORE-8  R-4 WD-22 2033 CORE-8  R-4 WD-23 2034CORE-8  R-4 WD-24 2035 CORE-8  R-4 WD-25 2036 CORE-8  R-5 WD-11 2037CORE-8  R-5 WD-12 2038 CORE-8  R-5 WD-13 2039 CORE-8  R-5 WD-14 2040CORE-8  R-5 WD-15 2041 CORE-8  R-5 WD-16 2042 CORE-8  R-5 WD-17 2043CORE-8  R-5 WD-18 2044 CORE-8  R-5 WD-19 2045 CORE-8  R-5 WD-20 2046CORE-8  R-5 WD-21 2047 CORE-8  R-5 WD-22 2048 CORE-8  R-5 WD-23 2049CORE-8  R-5 WD-24 2050 CORE-8  R-5 WD-25 2051 CORE-9  R-1 WD-11 2052CORE-9  R-1 WD-12 2053 CORE-9  R-1 WD-13 2054 CORE-9  R-1 WD-14 2055CORE-9  R-1 WD-15 2056 CORE-9  R-1 WD-16 2057 CORE-9  R-1 WD-17 2058CORE-9  R-1 WD-18 2059 CORE-9  R-1 WD-19 2060 CORE-9  R-1 WD-20 2061CORE-9  R-1 WD-21 2062 CORE-9  R-1 WD-22 2063 CORE-9  R-1 WD-23 2064CORE-9  R-1 WD-24 2065 CORE-9  R-1 WD-25 2066 CORE-9  R-2 WD-11 2067CORE-9  R-2 WD-12 2068 CORE-9  R-2 WD-13 2069 CORE-9  R-2 WD-14 2070CORE-9  R-2 WD-15 2071 CORE-9  R-2 WD-16 2072 CORE-9  R-2 WD-17 2073CORE-9  R-2 WD-18 2074 CORE-9  R-2 WD-19 2075 CORE-9  R-2 WD-20 2076CORE-9  R-2 WD-21 2077 CORE-9  R-2 WD-22 2078 CORE-9  R-2 WD-23 2079CORE-9  R-2 WD-24 2080 CORE-9  R-2 WD-25 2081 CORE-9  R-3 WD-11 2082CORE-9  R-3 WD-12 2083 CORE-9  R-3 WD-13 2084 CORE-9  R-3 WD-14 2085CORE-9  R-3 WD-15 2086 CORE-9  R-3 WD-16 2087 CORE-9  R-3 WD-17 2088CORE-9  R-3 WD-18 2089 CORE-9  R-3 WD-19 2090 CORE-9  R-3 WD-20 2091CORE-9  R-3 WD-21 2092 CORE-9  R-3 WD-22 2093 CORE-9  R-3 WD-23 2094CORE-9  R-3 WD-24 2095 CORE-9  R-3 WD-25 2096 CORE-9  R-4 WD-11 2097CORE-9  R-4 WD-12 2098 CORE-9  R-4 WD-13 2099 CORE-9  R-4 WD-14 2100CORE-9  R-4 WD-15 2101 CORE-9  R-4 WD-16 2102 CORE-9  R-4 WD-17 2103CORE-9  R-4 WD-18 2104 CORE-9  R-4 WD-19 2105 CORE-9  R-4 WD-20 2106CORE-9  R-4 WD-21 2107 CORE-9  R-4 WD-22 2108 CORE-9  R-4 WD-23 2109CORE-9  R-4 WD-24 2110 CORE-9  R-4 WD-25 2111 CORE-9  R-5 WD-11 2112CORE-9  R-5 WD-12 2113 CORE-9  R-5 WD-13 2114 CORE-9  R-5 WD-14 2115CORE-9  R-5 WD-15 2116 CORE-9  R-5 WD-16 2117 CORE-9  R-5 WD-17 2118CORE-9  R-5 WD-18 2119 CORE-9  R-5 WD-19 2120 CORE-9  R-5 WD-20 2121CORE-9  R-5 WD-21 2122 CORE-9  R-5 WD-22 2123 CORE-9  R-5 WD-23 2124CORE-9  R-5 WD-24 2125 CORE-9  R-5 WD-25 2126 CORE-10 R-1 WD-11 2127CORE-10 R-1 WD-12 2128 CORE-10 R-1 WD-13 2129 CORE-10 R-1 WD-14 2130CORE-10 R-1 WD-15 2131 CORE-10 R-1 WD-16 2132 CORE-10 R-1 WD-17 2133CORE-10 R-1 WD-18 2134 CORE-10 R-1 WD-19 2135 CORE-10 R-1 WD-20 2136CORE-10 R-1 WD-21 2137 CORE-10 R-1 WD-22 2138 CORE-10 R-1 WD-23 2139CORE-10 R-1 WD-24 2140 CORE-10 R-1 WD-25 2141 CORE-10 R-2 WD-11 2142CORE-10 R-2 WD-12 2143 CORE-10 R-2 WD-13 2144 CORE-10 R-2 WD-14 2145CORE-10 R-2 WD-15 2146 CORE-10 R-2 WD-16 2147 CORE-10 R-2 WD-17 2148CORE-10 R-2 WD-18 2149 CORE-10 R-2 WD-19 2150 CORE-10 R-2 WD-20 2151CORE-10 R-2 WD-21 2152 CORE-10 R-2 WD-22 2153 CORE-10 R-2 WD-23 2154CORE-10 R-2 WD-24 2155 CORE-10 R-2 WD-25 2156 CORE-10 R-3 WD-11 2157CORE-10 R-3 WD-12 2158 CORE-10 R-3 WD-13 2159 CORE-10 R-3 WD-14 2160CORE-10 R-3 WD-15 2161 CORE-10 R-3 WD-16 2162 CORE-10 R-3 WD-17 2163CORE-10 R-3 WD-18 2164 CORE-10 R-3 WD-19 2165 CORE-10 R-3 WD-20 2166CORE-10 R-3 WD-21 2167 CORE-10 R-3 WD-22 2168 CORE-10 R-3 WD-23 2169CORE-10 R-3 WD-24 2170 CORE-10 R-3 WD-25 2171 CORE-10 R-4 WD-11 2172CORE-10 R-4 WD-12 2173 CORE-10 R-4 WD-13 2174 CORE-10 R-4 WD-14 2175CORE-10 R-4 WD-15 2176 CORE-10 R-4 WD-16 2177 CORE-10 R-4 WD-17 2178CORE-10 R-4 WD-18 2179 CORE-10 R-4 WD-19 2180 CORE-10 R-4 WD-20 2181CORE-10 R-4 WD-21 2182 CORE-10 R-4 WD-22 2183 CORE-10 R-4 WD-23 2184CORE-10 R-4 WD-24 2185 CORE-10 R-4 WD-25 2186 CORE-10 R-5 WD-11 2187CORE-10 R-5 WD-12 2188 CORE-10 R-5 WD-13 2189 CORE-10 R-5 WD-14 2190CORE-10 R-5 WD-15 2191 CORE-10 R-5 WD-16 2192 CORE-10 R-5 WD-17 2193CORE-10 R-5 WD-18 2194 CORE-10 R-5 WD-19 2195 CORE-10 R-5 WD-20 2196CORE-10 R-5 WD-21 2197 CORE-10 R-5 WD-22 2198 CORE-10 R-5 WD-23 2199CORE-10 R-5 WD-24 2200 CORE-10 R-5 WD-25 2201 CORE-11 R-1 WD-11 2202CORE-11 R-1 WD-12 2203 CORE-11 R-1 WD-13 2204 CORE-11 R-1 WD-14 2205CORE-11 R-1 WD-15 2206 CORE-11 R-1 WD-16 2207 CORE-11 R-1 WD-17 2208CORE-11 R-1 WD-18 2209 CORE-11 R-1 WD-19 2210 CORE-11 R-1 WD-20 2211CORE-11 R-1 WD-21 2212 CORE-11 R-1 WD-22 2213 CORE-11 R-1 WD-23 2214CORE-11 R-1 WD-24 2215 CORE-11 R-1 WD-25 2216 CORE-11 R-2 WD-11 2217CORE-11 R-2 WD-12 2218 CORE-11 R-2 WD-13 2219 CORE-11 R-2 WD-14 2220CORE-11 R-2 WD-15 2221 CORE-11 R-2 WD-16 2222 CORE-11 R-2 WD-17 2223CORE-11 R-2 WD-18 2224 CORE-11 R-2 WD-19 2225 CORE-11 R-2 WD-20 2226CORE-11 R-2 WD-21 2227 CORE-11 R-2 WD-22 2228 CORE-11 R-2 WD-23 2229CORE-11 R-2 WD-24 2230 CORE-11 R-2 WD-25 2231 CORE-11 R-3 WD-11 2232CORE-11 R-3 WD-12 2233 CORE-11 R-3 WD-13 2234 CORE-11 R-3 WD-14 2235CORE-11 R-3 WD-15 2236 CORE-11 R-3 WD-16 2237 CORE-11 R-3 WD-17 2238CORE-11 R-3 WD-18 2239 CORE-11 R-3 WD-19 2240 CORE-11 R-3 WD-20 2241CORE-11 R-3 WD-21 2242 CORE-11 R-3 WD-22 2243 CORE-11 R-3 WD-23 2244CORE-11 R-3 WD-24 2245 CORE-11 R-3 WD-25 2246 CORE-11 R-4 WD-11 2247CORE-11 R-4 WD-12 2248 CORE-11 R-4 WD-13 2249 CORE-11 R-4 WD-14 2250CORE-11 R-4 WD-15 2251 CORE-11 R-4 WD-16 2252 CORE-11 R-4 WD-17 2253CORE-11 R-4 WD-18 2254 CORE-11 R-4 WD-19 2255 CORE-11 R-4 WD-20 2256CORE-11 R-4 WD-21 2257 CORE-11 R-4 WD-22 2258 CORE-11 R-4 WD-23 2259CORE-11 R-4 WD-24 2260 CORE-11 R-4 WD-25 2261 CORE-11 R-5 WD-11 2262CORE-11 R-5 WD-12 2263 CORE-11 R-5 WD-13 2264 CORE-11 R-5 WD-14 2265CORE-11 R-5 WD-15 2266 CORE-11 R-5 WD-16 2267 CORE-11 R-5 WD-17 2268CORE-11 R-5 WD-18 2269 CORE-11 R-5 WD-19 2270 CORE-11 R-5 WD-20 2271CORE-11 R-5 WD-21 2272 CORE-11 R-5 WD-22 2273 CORE-11 R-5 WD-23 2274CORE-11 R-5 WD-24 2275 CORE-11 R-5 WD-25 2276 CORE-12 R-1 WD-11 2277CORE-12 R-1 WD-12 2278 CORE-12 R-1 WD-13 2279 CORE-12 R-1 WD-14 2280CORE-12 R-1 WD-15 2281 CORE-12 R-1 WD-16 2282 CORE-12 R-1 WD-17 2283CORE-12 R-1 WD-18 2284 CORE-12 R-1 WD-19 2285 CORE-12 R-1 WD-20 2286CORE-12 R-1 WD-21 2287 CORE-12 R-1 WD-22 2288 CORE-12 R-1 WD-23 2289CORE-12 R-1 WD-24 2290 CORE-12 R-1 WD-25 2291 CORE-12 R-2 WD-11 2292CORE-12 R-2 WD-12 2293 CORE-12 R-2 WD-13 2294 CORE-12 R-2 WD-14 2295CORE-12 R-2 WD-15 2296 CORE-12 R-2 WD-16 2297 CORE-12 R-2 WD-17 2298CORE-12 R-2 WD-18 2299 CORE-12 R-2 WD-19 2300 CORE-12 R-2 WD-20 2301CORE-12 R-2 WD-21 2302 CORE-12 R-2 WD-22 2303 CORE-12 R-2 WD-23 2304CORE-12 R-2 WD-24 2305 CORE-12 R-2 WD-25 2306 CORE-12 R-3 WD-11 2307CORE-12 R-3 WD-12 2308 CORE-12 R-3 WD-13 2309 CORE-12 R-3 WD-14 2310CORE-12 R-3 WD-15 2311 CORE-12 R-3 WD-16 2312 CORE-12 R-3 WD-17 2313CORE-12 R-3 WD-18 2314 CORE-12 R-3 WD-19 2315 CORE-12 R-3 WD-20 2316CORE-12 R-3 WD-21 2317 CORE-12 R-3 WD-22 2318 CORE-12 R-3 WD-23 2319CORE-12 R-3 WD-24 2320 CORE-12 R-3 WD-25 2321 CORE-12 R-4 WD-11 2322CORE-12 R-4 WD-12 2323 CORE-12 R-4 WD-13 2324 CORE-12 R-4 WD-14 2325CORE-12 R-4 WD-15 2326 CORE-12 R-4 WD-16 2327 CORE-12 R-4 WD-17 2328CORE-12 R-4 WD-18 2329 CORE-12 R-4 WD-19 2330 CORE-12 R-4 WD-20 2331CORE-12 R-4 WD-21 2332 CORE-12 R-4 WD-22 2333 CORE-12 R-4 WD-23 2334CORE-12 R-4 WD-24 2335 CORE-12 R-4 WD-25 2336 CORE-12 R-5 WD-11 2337CORE-12 R-5 WD-12 2338 CORE-12 R-5 WD-13 2339 CORE-12 R-5 WD-14 2340CORE-12 R-5 WD-15 2341 CORE-12 R-5 WD-16 2342 CORE-12 R-5 WD-17 2343CORE-12 R-5 WD-18 2344 CORE-12 R-5 WD-19 2345 CORE-12 R-5 WD-20 2346CORE-12 R-5 WD-21 2347 CORE-12 R-5 WD-22 2348 CORE-12 R-5 WD-23 2349CORE-12 R-5 WD-24 2350 CORE-12 R-5 WD-25 2351 CORE-13 R-1 WD-11 2352CORE-13 R-1 WD-12 2353 CORE-13 R-1 WD-13 2354 CORE-13 R-1 WD-14 2355CORE-13 R-1 WD-15 2356 CORE-13 R-1 WD-16 2357 CORE-13 R-1 WD-17 2358CORE-13 R-1 WD-18 2359 CORE-13 R-1 WD-19 2360 CORE-13 R-1 WD-20 2361CORE-13 R-1 WD-21 2362 CORE-13 R-1 WD-22 2363 CORE-13 R-1 WD-23 2364CORE-13 R-1 WD-24 2365 CORE-13 R-1 WD-25 2366 CORE-13 R-2 WD-11 2367CORE-13 R-2 WD-12 2368 CORE-13 R-2 WD-13 2369 CORE-13 R-2 WD-14 2370CORE-13 R-2 WD-15 2371 CORE-13 R-2 WD-16 2372 CORE-13 R-2 WD-17 2373CORE-13 R-2 WD-18 2374 CORE-13 R-2 WD-19 2375 CORE-13 R-2 WD-20 2376CORE-13 R-2 WD-21 2377 CORE-13 R-2 WD-22 2378 CORE-13 R-2 WD-23 2379CORE-13 R-2 WD-24 2380 CORE-13 R-2 WD-25 2381 CORE-13 R-3 WD-11 2382CORE-13 R-3 WD-12 2383 CORE-13 R-3 WD-13 2384 CORE-13 R-3 WD-14 2385CORE-13 R-3 WD-15 2386 CORE-13 R-3 WD-16 2387 CORE-13 R-3 WD-17 2388CORE-13 R-3 WD-18 2389 CORE-13 R-3 WD-19 2390 CORE-13 R-3 WD-20 2391CORE-13 R-3 WD-21 2392 CORE-13 R-3 WD-22 2393 CORE-13 R-3 WD-23 2394CORE-13 R-3 WD-24 2395 CORE-13 R-3 WD-25 2396 CORE-13 R-4 WD-11 2397CORE-13 R-4 WD-12 2398 CORE-13 R-4 WD-13 2399 CORE-13 R-4 WD-14 2400CORE-13 R-4 WD-15 2401 CORE-13 R-4 WD-16 2402 CORE-13 R-4 WD-17 2403CORE-13 R-4 WD-18 2404 CORE-13 R-4 WD-19 2405 CORE-13 R-4 WD-20 2406CORE-13 R-4 WD-21 2407 CORE-13 R-4 WD-22 2408 CORE-13 R-4 WD-23 2409CORE-13 R-4 WD-24 2410 CORE-13 R-4 WD-25 2411 CORE-13 R-5 WD-11 2412CORE-13 R-5 WD-12 2413 CORE-13 R-5 WD-13 2414 CORE-13 R-5 WD-14 2415CORE-13 R-5 WD-15 2416 CORE-13 R-5 WD-16 2417 CORE-13 R-5 WD-17 2418CORE-13 R-5 WD-18 2419 CORE-13 R-5 WD-19 2420 CORE-13 R-5 WD-20 2421CORE-13 R-5 WD-21 2422 CORE-13 R-5 WD-22 2423 CORE-13 R-5 WD-23 2424CORE-13 R-5 WD-24 2425 CORE-13 R-5 WD-25 2426 CORE-14 R-1 WD-11 2427CORE-14 R-1 WD-12 2428 CORE-14 R-1 WD-13 2429 CORE-14 R-1 WD-14 2430CORE-14 R-1 WD-15 2431 CORE-14 R-1 WD-16 2432 CORE-14 R-1 WD-17 2433CORE-14 R-1 WD-18 2434 CORE-14 R-1 WD-19 2435 CORE-14 R-1 WD-20 2436CORE-14 R-1 WD-21 2437 CORE-14 R-1 WD-22 2438 CORE-14 R-1 WD-23 2439CORE-14 R-1 WD-24 2440 CORE-14 R-1 WD-25 2441 CORE-14 R-2 WD-11 2442CORE-14 R-2 WD-12 2443 CORE-14 R-2 WD-13 2444 CORE-14 R-2 WD-14 2445CORE-14 R-2 WD-15 2446 CORE-14 R-2 WD-16 2447 CORE-14 R-2 WD-17 2448CORE-14 R-2 WD-18 2449 CORE-14 R-2 WD-19 2450 CORE-14 R-2 WD-20 2451CORE-14 R-2 WD-21 2452 CORE-14 R-2 WD-22 2453 CORE-14 R-2 WD-23 2454CORE-14 R-2 WD-24 2455 CORE-14 R-2 WD-25 2456 CORE-14 R-3 WD-11 2457CORE-14 R-3 WD-12 2458 CORE-14 R-3 WD-13 2459 CORE-14 R-3 WD-14 2460CORE-14 R-3 WD-15 2461 CORE-14 R-3 WD-16 2462 CORE-14 R-3 WD-17 2463CORE-14 R-3 WD-18 2464 CORE-14 R-3 WD-19 2465 CORE-14 R-3 WD-20 2466CORE-14 R-3 WD-21 2467 CORE-14 R-3 WD-22 2468 CORE-14 R-3 WD-23 2469CORE-14 R-3 WD-24 2470 CORE-14 R-3 WD-25 2471 CORE-14 R-4 WD-11 2472CORE-14 R-4 WD-12 2473 CORE-14 R-4 WD-13 2474 CORE-14 R-4 WD-14 2475CORE-14 R-4 WD-15 2476 CORE-14 R-4 WD-16 2477 CORE-14 R-4 WD-17 2478CORE-14 R-4 WD-18 2479 CORE-14 R-4 WD-19 2480 CORE-14 R-4 WD-20 2481CORE-14 R-4 WD-21 2482 CORE-14 R-4 WD-22 2483 CORE-14 R-4 WD-23 2484CORE-14 R-4 WD-24 2485 CORE-14 R-4 WD-25 2486 CORE-14 R-5 WD-11 2487CORE-14 R-5 WD-12 2488 CORE-14 R-5 WD-13 2489 CORE-14 R-5 WD-14 2490CORE-14 R-5 WD-15 2491 CORE-14 R-5 WD-16 2492 CORE-14 R-5 WD-17 2493CORE-14 R-5 WD-18 2494 CORE-14 R-5 WD-19 2495 CORE-14 R-5 WD-20 2496CORE-14 R-5 WD-21 2497 CORE-14 R-5 WD-22 2498 CORE-14 R-5 WD-23 2499CORE-14 R-5 WD-24 2500 CORE-14 R-5 WD-25 2501 CORE-15 R-1 WD-11 2502CORE-15 R-1 WD-12 2503 CORE-15 R-1 WD-13 2504 CORE-15 R-1 WD-14 2505CORE-15 R-1 WD-15 2506 CORE-15 R-1 WD-16 2507 CORE-15 R-1 WD-17 2508CORE-15 R-1 WD-18 2509 CORE-15 R-1 WD-19 2510 CORE-15 R-1 WD-20 2511CORE-15 R-1 WD-21 2512 CORE-15 R-1 WD-22 2513 CORE-15 R-1 WD-23 2514CORE-15 R-1 WD-24 2515 CORE-15 R-1 WD-25 2516 CORE-15 R-2 WD-11 2517CORE-15 R-2 WD-12 2518 CORE-15 R-2 WD-13 2519 CORE-15 R-2 WD-14 2520CORE-15 R-2 WD-15 2521 CORE-15 R-2 WD-16 2522 CORE-15 R-2 WD-17 2523CORE-15 R-2 WD-18 2524 CORE-15 R-2 WD-19 2525 CORE-15 R-2 WD-20 2526CORE-15 R-2 WD-21 2527 CORE-15 R-2 WD-22 2528 CORE-15 R-2 WD-23 2529CORE-15 R-2 WD-24 2530 CORE-15 R-2 WD-25 2531 CORE-15 R-3 WD-11 2532CORE-15 R-3 WD-12 2533 CORE-15 R-3 WD-13 2534 CORE-15 R-3 WD-14 2535CORE-15 R-3 WD-15 2536 CORE-15 R-3 WD-16 2537 CORE-15 R-3 WD-17 2538CORE-15 R-3 WD-18 2539 CORE-15 R-3 WD-19 2540 CORE-15 R-3 WD-20 2541CORE-15 R-3 WD-21 2542 CORE-15 R-3 WD-22 2543 CORE-15 R-3 WD-23 2544CORE-15 R-3 WD-24 2545 CORE-15 R-3 WD-25 2546 CORE-15 R-4 WD-11 2547CORE-15 R-4 WD-12 2548 CORE-15 R-4 WD-13 2549 CORE-15 R-4 WD-14 2550CORE-15 R-4 WD-15 2551 CORE-15 R-4 WD-16 2552 CORE-15 R-4 WD-17 2553CORE-15 R-4 WD-18 2554 CORE-15 R-4 WD-19 2555 CORE-15 R-4 WD-20 2556CORE-15 R-4 WD-21 2557 CORE-15 R-4 WD-22 2558 CORE-15 R-4 WD-23 2559CORE-15 R-4 WD-24 2560 CORE-15 R-4 WD-25 2561 CORE-15 R-5 WD-11 2562CORE-15 R-5 WD-12 2563 CORE-15 R-5 WD-13 2564 CORE-15 R-5 WD-14 2565CORE-15 R-5 WD-15 2566 CORE-15 R-5 WD-16 2567 CORE-15 R-5 WD-17 2568CORE-15 R-5 WD-18 2569 CORE-15 R-5 WD-19 2570 CORE-15 R-5 WD-20 2571CORE-15 R-5 WD-21 2572 CORE-15 R-5 WD-22 2573 CORE-15 R-5 WD-23 2574CORE-15 R-5 WD-24 2575 CORE-15 R-5 WD-25 2576 CORE-16 R-1 WD-11 2577CORE-16 R-1 WD-12 2578 CORE-16 R-1 WD-13 2579 CORE-16 R-1 WD-14 2580CORE-16 R-1 WD-15 2581 CORE-16 R-1 WD-16 2582 CORE-16 R-1 WD-17 2583CORE-16 R-1 WD-18 2584 CORE-16 R-1 WD-19 2585 CORE-16 R-1 WD-20 2586CORE-16 R-1 WD-21 2587 CORE-16 R-1 WD-22 2588 CORE-16 R-1 WD-23 2589CORE-16 R-1 WD-24 2590 CORE-16 R-1 WD-25 2591 CORE-16 R-2 WD-11 2592CORE-16 R-2 WD-12 2593 CORE-16 R-2 WD-13 2594 CORE-16 R-2 WD-14 2595CORE-16 R-2 WD-15 2596 CORE-16 R-2 WD-16 2597 CORE-16 R-2 WD-17 2598CORE-16 R-2 WD-18 2599 CORE-16 R-2 WD-19 2600 CORE-16 R-2 WD-20 2601CORE-16 R-2 WD-21 2602 CORE-16 R-2 WD-22 2603 CORE-16 R-2 WD-23 2604CORE-16 R-2 WD-24 2605 CORE-16 R-2 WD-25 2606 CORE-16 R-3 WD-11 2607CORE-16 R-3 WD-12 2608 CORE-16 R-3 WD-13 2609 CORE-16 R-3 WD-14 2610CORE-16 R-3 WD-15 2611 CORE-16 R-3 WD-16 2612 CORE-16 R-3 WD-17 2613CORE-16 R-3 WD-18 2614 CORE-16 R-3 WD-19 2615 CORE-16 R-3 WD-20 2616CORE-16 R-3 WD-21 2617 CORE-16 R-3 WD-22 2618 CORE-16 R-3 WD-23 2619CORE-16 R-3 WD-24 2620 CORE-16 R-3 WD-25 2621 CORE-16 R-4 WD-11 2622CORE-16 R-4 WD-12 2623 CORE-16 R-4 WD-13 2624 CORE-16 R-4 WD-14 2625CORE-16 R-4 WD-15 2626 CORE-16 R-4 WD-16 2627 CORE-16 R-4 WD-17 2628CORE-16 R-4 WD-18 2629 CORE-16 R-4 WD-19 2630 CORE-16 R-4 WD-20 2631CORE-16 R-4 WD-21 2632 CORE-16 R-4 WD-22 2633 CORE-16 R-4 WD-23 2634CORE-16 R-4 WD-24 2635 CORE-16 R-4 WD-25 2636 CORE-16 R-5 WD-11 2637CORE-16 R-5 WD-12 2638 CORE-16 R-5 WD-13 2639 CORE-16 R-5 WD-14 2640CORE-16 R-5 WD-15 2641 CORE-16 R-5 WD-16 2642 CORE-16 R-5 WD-17 2643CORE-16 R-5 WD-18 2644 CORE-16 R-5 WD-19 2645 CORE-16 R-5 WD-20 2646CORE-16 R-5 WD-21 2647 CORE-16 R-5 WD-22 2648 CORE-16 R-5 WD-23 2649CORE-16 R-5 WD-24 2650 CORE-16 R-5 WD-25 2651 CORE-17 R-1 WD-11 2652CORE-17 R-1 WD-12 2653 CORE-17 R-1 WD-13 2654 CORE-17 R-1 WD-14 2655CORE-17 R-1 WD-15 2656 CORE-17 R-1 WD-16 2657 CORE-17 R-1 WD-17 2658CORE-17 R-1 WD-18 2659 CORE-17 R-1 WD-19 2660 CORE-17 R-1 WD-20 2661CORE-17 R-1 WD-21 2662 CORE-17 R-1 WD-22 2663 CORE-17 R-1 WD-23 2664CORE-17 R-1 WD-24 2665 CORE-17 R-1 WD-25 2666 CORE-17 R-2 WD-11 2667CORE-17 R-2 WD-12 2668 CORE-17 R-2 WD-13 2669 CORE-17 R-2 WD-14 2670CORE-17 R-2 WD-15 2671 CORE-17 R-2 WD-16 2672 CORE-17 R-2 WD-17 2673CORE-17 R-2 WD-18 2674 CORE-17 R-2 WD-19 2675 CORE-17 R-2 WD-20 2676CORE-17 R-2 WD-21 2677 CORE-17 R-2 WD-22 2678 CORE-17 R-2 WD-23 2679CORE-17 R-2 WD-24 2680 CORE-17 R-2 WD-25 2681 CORE-17 R-3 WD-11 2682CORE-17 R-3 WD-12 2683 CORE-17 R-3 WD-13 2684 CORE-17 R-3 WD-14 2685CORE-17 R-3 WD-15 2686 CORE-17 R-3 WD-16 2687 CORE-17 R-3 WD-17 2688CORE-17 R-3 WD-18 2689 CORE-17 R-3 WD-19 2690 CORE-17 R-3 WD-20 2691CORE-17 R-3 WD-21 2692 CORE-17 R-3 WD-22 2693 CORE-17 R-3 WD-23 2694CORE-17 R-3 WD-24 2695 CORE-17 R-3 WD-25 2696 CORE-17 R-4 WD-11 2697CORE-17 R-4 WD-12 2698 CORE-17 R-4 WD-13 2699 CORE-17 R-4 WD-14 2700CORE-17 R-4 WD-15 2701 CORE-17 R-4 WD-16 2702 CORE-17 R-4 WD-17 2703CORE-17 R-4 WD-18 2704 CORE-17 R-4 WD-19 2705 CORE-17 R-4 WD-20 2706CORE-17 R-4 WD-21 2707 CORE-17 R-4 WD-22 2708 CORE-17 R-4 WD-23 2709CORE-17 R-4 WD-24 2710 CORE-17 R-4 WD-25 2711 CORE-17 R-5 WD-11 2712CORE-17 R-5 WD-12 2713 CORE-17 R-5 WD-13 2714 CORE-17 R-5 WD-14 2715CORE-17 R-5 WD-15 2716 CORE-17 R-5 WD-16 2717 CORE-17 R-5 WD-17 2718CORE-17 R-5 WD-18 2719 CORE-17 R-5 WD-19 2720 CORE-17 R-5 WD-20 2721CORE-17 R-5 WD-21 2722 CORE-17 R-5 WD-22 2723 CORE-17 R-5 WD-23 2724CORE-17 R-5 WD-24 2725 CORE-17 R-5 WD-25 2726 CORE-18 R-1 WD-11 2727CORE-18 R-1 WD-12 2728 CORE-18 R-1 WD-13 2729 CORE-18 R-1 WD-14 2730CORE-18 R-1 WD-15 2731 CORE-18 R-1 WD-16 2732 CORE-18 R-1 WD-17 2733CORE-18 R-1 WD-18 2734 CORE-18 R-1 WD-19 2735 CORE-18 R-1 WD-20 2736CORE-18 R-1 WD-21 2737 CORE-18 R-1 WD-22 2738 CORE-18 R-1 WD-23 2739CORE-18 R-1 WD-24 2740 CORE-18 R-1 WD-25 2741 CORE-18 R-2 WD-11 2742CORE-18 R-2 WD-12 2743 CORE-18 R-2 WD-13 2744 CORE-18 R-2 WD-14 2745CORE-18 R-2 WD-15 2746 CORE-18 R-2 WD-16 2747 CORE-18 R-2 WD-17 2748CORE-18 R-2 WD-18 2749 CORE-18 R-2 WD-19 2750 CORE-18 R-2 WD-20 2751CORE-18 R-2 WD-21 2752 CORE-18 R-2 WD-22 2753 CORE-18 R-2 WD-23 2754CORE-18 R-2 WD-24 2755 CORE-18 R-2 WD-25 2756 CORE-18 R-3 WD-11 2757CORE-18 R-3 WD-12 2758 CORE-18 R-3 WD-13 2759 CORE-18 R-3 WD-14 2760CORE-18 R-3 WD-15 2761 CORE-18 R-3 WD-16 2762 CORE-18 R-3 WD-17 2763CORE-18 R-3 WD-18 2764 CORE-18 R-3 WD-19 2765 CORE-18 R-3 WD-20 2766CORE-18 R-3 WD-21 2767 CORE-18 R-3 WD-22 2768 CORE-18 R-3 WD-23 2769CORE-18 R-3 WD-24 2770 CORE-18 R-3 WD-25 2771 CORE-18 R-4 WD-11 2772CORE-18 R-4 WD-12 2773 CORE-18 R-4 WD-13 2774 CORE-18 R-4 WD-14 2775CORE-18 R-4 WD-15 2776 CORE-18 R-4 WD-16 2777 CORE-18 R-4 WD-17 2778CORE-18 R-4 WD-18 2779 CORE-18 R-4 WD-19 2780 CORE-18 R-4 WD-20 2781CORE-18 R-4 WD-21 2782 CORE-18 R-4 WD-22 2783 CORE-18 R-4 WD-23 2784CORE-18 R-4 WD-24 2785 CORE-18 R-4 WD-25 2786 CORE-18 R-5 WD-11 2787CORE-18 R-5 WD-12 2788 CORE-18 R-5 WD-13 2789 CORE-18 R-5 WD-14 2790CORE-18 R-5 WD-15 2791 CORE-18 R-5 WD-16 2792 CORE-18 R-5 WD-17 2793CORE-18 R-5 WD-18 2794 CORE-18 R-5 WD-19 2795 CORE-18 R-5 WD-20 2796CORE-18 R-5 WD-21 2797 CORE-18 R-5 WD-22 2798 CORE-18 R-5 WD-23 2799CORE-18 R-5 WD-24 2800 CORE-18 R-5 WD-25 2801 CORE-19 R-1 WD-11 2802CORE-19 R-1 WD-12 2803 CORE-19 R-1 WD-13 2804 CORE-19 R-1 WD-14 2805CORE-19 R-1 WD-15 2806 CORE-19 R-1 WD-16 2807 CORE-19 R-1 WD-17 2808CORE-19 R-1 WD-18 2809 CORE-19 R-1 WD-19 2810 CORE-19 R-1 WD-20 2811CORE-19 R-1 WD-21 2812 CORE-19 R-1 WD-22 2813 CORE-19 R-1 WD-23 2814CORE-19 R-1 WD-24 2815 CORE-19 R-1 WD-25 2816 CORE-19 R-2 WD-11 2817CORE-19 R-2 WD-12 2818 CORE-19 R-2 WD-13 2819 CORE-19 R-2 WD-14 2820CORE-19 R-2 WD-15 2821 CORE-19 R-2 WD-16 2822 CORE-19 R-2 WD-17 2823CORE-19 R-2 WD-18 2824 CORE-19 R-2 WD-19 2825 CORE-19 R-2 WD-20 2826CORE-19 R-2 WD-21 2827 CORE-19 R-2 WD-22 2828 CORE-19 R-2 WD-23 2829CORE-19 R-2 WD-24 2830 CORE-19 R-2 WD-25 2831 CORE-19 R-3 WD-11 2832CORE-19 R-3 WD-12 2833 CORE-19 R-3 WD-13 2834 CORE-19 R-3 WD-14 2835CORE-19 R-3 WD-15 2836 CORE-19 R-3 WD-16 2837 CORE-19 R-3 WD-17 2838CORE-19 R-3 WD-18 2839 CORE-19 R-3 WD-19 2840 CORE-19 R-3 WD-20 2841CORE-19 R-3 WD-21 2842 CORE-19 R-3 WD-22 2843 CORE-19 R-3 WD-23 2844CORE-19 R-3 WD-24 2845 CORE-19 R-3 WD-25 2846 CORE-19 R-4 WD-11 2847CORE-19 R-4 WD-12 2848 CORE-19 R-4 WD-13 2849 CORE-19 R-4 WD-14 2850CORE-19 R-4 WD-15 2851 CORE-19 R-4 WD-16 2852 CORE-19 R-4 WD-17 2853CORE-19 R-4 WD-18 2854 CORE-19 R-4 WD-19 2855 CORE-19 R-4 WD-20 2856CORE-19 R-4 WD-21 2857 CORE-19 R-4 WD-22 2858 CORE-19 R-4 WD-23 2859CORE-19 R-4 WD-24 2860 CORE-19 R-4 WD-25 2861 CORE-19 R-5 WD-11 2862CORE-19 R-5 WD-12 2863 CORE-19 R-5 WD-13 2864 CORE-19 R-5 WD-14 2865CORE-19 R-5 WD-15 2866 CORE-19 R-5 WD-16 2867 CORE-19 R-5 WD-17 2868CORE-19 R-5 WD-18 2869 CORE-19 R-5 WD-19 2870 CORE-19 R-5 WD-20 2871CORE-19 R-5 WD-21 2872 CORE-19 R-5 WD-22 2873 CORE-19 R-5 WD-23 2874CORE-19 R-5 WD-24 2875 CORE-19 R-5 WD-25 2876 CORE-20 R-1 WD-11 2877CORE-20 R-1 WD-12 2878 CORE-20 R-1 WD-13 2879 CORE-20 R-1 WD-14 2880CORE-20 R-1 WD-15 2881 CORE-20 R-1 WD-16 2882 CORE-20 R-1 WD-17 2883CORE-20 R-1 WD-18 2884 CORE-20 R-1 WD-19 2885 CORE-20 R-1 WD-20 2886CORE-20 R-1 WD-21 2887 CORE-20 R-1 WD-22 2888 CORE-20 R-1 WD-23 2889CORE-20 R-1 WD-24 2890 CORE-20 R-1 WD-25 2891 CORE-20 R-2 WD-11 2892CORE-20 R-2 WD-12 2893 CORE-20 R-2 WD-13 2894 CORE-20 R-2 WD-14 2895CORE-20 R-2 WD-15 2896 CORE-20 R-2 WD-16 2897 CORE-20 R-2 WD-17 2898CORE-20 R-2 WD-18 2899 CORE-20 R-2 WD-19 2900 CORE-20 R-2 WD-20 2901CORE-20 R-2 WD-21 2902 CORE-20 R-2 WD-22 2903 CORE-20 R-2 WD-23 2904CORE-20 R-2 WD-24 2905 CORE-20 R-2 WD-25 2906 CORE-20 R-3 WD-11 2907CORE-20 R-3 WD-12 2908 CORE-20 R-3 WD-13 2909 CORE-20 R-3 WD-14 2910CORE-20 R-3 WD-15 2911 CORE-20 R-3 WD-16 2912 CORE-20 R-3 WD-17 2913CORE-20 R-3 WD-18 2914 CORE-20 R-3 WD-19 2915 CORE-20 R-3 WD-20 2916CORE-20 R-3 WD-21 2917 CORE-20 R-3 WD-22 2918 CORE-20 R-3 WD-23 2919CORE-20 R-3 WD-24 2920 CORE-20 R-3 WD-25 2921 CORE-20 R-4 WD-11 2922CORE-20 R-4 WD-12 2923 CORE-20 R-4 WD-13 2924 CORE-20 R-4 WD-14 2925CORE-20 R-4 WD-15 2926 CORE-20 R-4 WD-16 2927 CORE-20 R-4 WD-17 2928CORE-20 R-4 WD-18 2929 CORE-20 R-4 WD-19 2930 CORE-20 R-4 WD-20 2931CORE-20 R-4 WD-21 2932 CORE-20 R-4 WD-22 2933 CORE-20 R-4 WD-23 2934CORE-20 R-4 WD-24 2935 CORE-20 R-4 WD-25 2936 CORE-20 R-5 WD-11 2937CORE-20 R-5 WD-12 2938 CORE-20 R-5 WD-13 2939 CORE-20 R-5 WD-14 2940CORE-20 R-5 WD-15 2941 CORE-20 R-5 WD-16 2942 CORE-20 R-5 WD-17 2943CORE-20 R-5 WD-18 2944 CORE-20 R-5 WD-19 2945 CORE-20 R-5 WD-20 2946CORE-20 R-5 WD-21 2947 CORE-20 R-5 WD-22 2948 CORE-20 R-5 WD-23 2949CORE-20 R-5 WD-24 2950 CORE-20 R-5 WD-25 2951 CORE-21 R-1 WD-11 2952CORE-21 R-1 WD-12 2953 CORE-21 R-1 WD-13 2954 CORE-21 R-1 WD-14 2955CORE-21 R-1 WD-15 2956 CORE-21 R-1 WD-16 2957 CORE-21 R-1 WD-17 2958CORE-21 R-1 WD-18 2959 CORE-21 R-1 WD-19 2960 CORE-21 R-1 WD-20 2961CORE-21 R-1 WD-21 2962 CORE-21 R-1 WD-22 2963 CORE-21 R-1 WD-23 2964CORE-21 R-1 WD-24 2965 CORE-21 R-1 WD-25 2966 CORE-21 R-2 WD-11 2967CORE-21 R-2 WD-12 2968 CORE-21 R-2 WD-13 2969 CORE-21 R-2 WD-14 2970CORE-21 R-2 WD-15 2971 CORE-21 R-2 WD-16 2972 CORE-21 R-2 WD-17 2973CORE-21 R-2 WD-18 2974 CORE-21 R-2 WD-19 2975 CORE-21 R-2 WD-20 2976CORE-21 R-2 WD-21 2977 CORE-21 R-2 WD-22 2978 CORE-21 R-2 WD-23 2979CORE-21 R-2 WD-24 2980 CORE-21 R-2 WD-25 2981 CORE-21 R-3 WD-11 2982CORE-21 R-3 WD-12 2983 CORE-21 R-3 WD-13 2984 CORE-21 R-3 WD-14 2985CORE-21 R-3 WD-15 2986 CORE-21 R-3 WD-16 2987 CORE-21 R-3 WD-17 2988CORE-21 R-3 WD-18 2989 CORE-21 R-3 WD-19 2990 CORE-21 R-3 WD-20 2991CORE-21 R-3 WD-21 2992 CORE-21 R-3 WD-22 2993 CORE-21 R-3 WD-23 2994CORE-21 R-3 WD-24 2995 CORE-21 R-3 WD-25 2996 CORE-21 R-4 WD-11 2997CORE-21 R-4 WD-12 2998 CORE-21 R-4 WD-13 2999 CORE-21 R-4 WD-14 3000CORE-21 R-4 WD-15 3001 CORE-21 R-4 WD-16 3002 CORE-21 R-4 WD-17 3003CORE-21 R-4 WD-18 3004 CORE-21 R-4 WD-19 3005 CORE-21 R-4 WD-20 3006CORE-21 R-4 WD-21 3007 CORE-21 R-4 WD-22 3008 CORE-21 R-4 WD-23 3009CORE-21 R-4 WD-24 3010 CORE-21 R-4 WD-25 3011 CORE-21 R-5 WD-11 3012CORE-21 R-5 WD-12 3013 CORE-21 R-5 WD-13 3014 CORE-21 R-5 WD-14 3015CORE-21 R-5 WD-15 3016 CORE-21 R-5 WD-16 3017 CORE-21 R-5 WD-17 3018CORE-21 R-5 WD-18 3019 CORE-21 R-5 WD-19 3020 CORE-21 R-5 WD-20 3021CORE-21 R-5 WD-21 3022 CORE-21 R-5 WD-22 3023 CORE-21 R-5 WD-23 3024CORE-21 R-5 WD-24 3025 CORE-21 R-5 WD-25 3026 CORE-22 R-1 WD-11 3027CORE-22 R-1 WD-12 3028 CORE-22 R-1 WD-13 3029 CORE-22 R-1 WD-14 3030CORE-22 R-1 WD-15 3031 CORE-22 R-1 WD-16 3032 CORE-22 R-1 WD-17 3033CORE-22 R-1 WD-18 3034 CORE-22 R-1 WD-19 3035 CORE-22 R-1 WD-20 3036CORE-22 R-1 WD-21 3037 CORE-22 R-1 WD-22 3038 CORE-22 R-1 WD-23 3039CORE-22 R-1 WD-24 3040 CORE-22 R-1 WD-25 3041 CORE-22 R-2 WD-11 3042CORE-22 R-2 WD-12 3043 CORE-22 R-2 WD-13 3044 CORE-22 R-2 WD-14 3045CORE-22 R-2 WD-15 3046 CORE-22 R-2 WD-16 3047 CORE-22 R-2 WD-17 3048CORE-22 R-2 WD-18 3049 CORE-22 R-2 WD-19 3050 CORE-22 R-2 WD-20 3051CORE-22 R-2 WD-21 3052 CORE-22 R-2 WD-22 3053 CORE-22 R-2 WD-23 3054CORE-22 R-2 WD-24 3055 CORE-22 R-2 WD-25 3056 CORE-22 R-3 WD-11 3057CORE-22 R-3 WD-12 3058 CORE-22 R-3 WD-13 3059 CORE-22 R-3 WD-14 3060CORE-22 R-3 WD-15 3061 CORE-22 R-3 WD-16 3062 CORE-22 R-3 WD-17 3063CORE-22 R-3 WD-18 3064 CORE-22 R-3 WD-19 3065 CORE-22 R-3 WD-20 3066CORE-22 R-3 WD-21 3067 CORE-22 R-3 WD-22 3068 CORE-22 R-3 WD-23 3069CORE-22 R-3 WD-24 3070 CORE-22 R-3 WD-25 3071 CORE-22 R-4 WD-11 3072CORE-22 R-4 WD-12 3073 CORE-22 R-4 WD-13 3074 CORE-22 R-4 WD-14 3075CORE-22 R-4 WD-15 3076 CORE-22 R-4 WD-16 3077 CORE-22 R-4 WD-17 3078CORE-22 R-4 WD-18 3079 CORE-22 R-4 WD-19 3080 CORE-22 R-4 WD-20 3081CORE-22 R-4 WD-21 3082 CORE-22 R-4 WD-22 3083 CORE-22 R-4 WD-23 3084CORE-22 R-4 WD-24 3085 CORE-22 R-4 WD-25 3086 CORE-22 R-5 WD-11 3087CORE-22 R-5 WD-12 3088 CORE-22 R-5 WD-13 3089 CORE-22 R-5 WD-14 3090CORE-22 R-5 WD-15 3091 CORE-22 R-5 WD-16 3092 CORE-22 R-5 WD-17 3093CORE-22 R-5 WD-18 3094 CORE-22 R-5 WD-19 3095 CORE-22 R-5 WD-20 3096CORE-22 R-5 WD-21 3097 CORE-22 R-5 WD-22 3098 CORE-22 R-5 WD-23 3099CORE-22 R-5 WD-24 3100 CORE-22 R-5 WD-25 3101 CORE-23 R-1 WD-11 3102CORE-23 R-1 WD-12 3103 CORE-23 R-1 WD-13 3104 CORE-23 R-1 WD-14 3105CORE-23 R-1 WD-15 3106 CORE-23 R-1 WD-16 3107 CORE-23 R-1 WD-17 3108CORE-23 R-1 WD-18 3109 CORE-23 R-1 WD-19 3110 CORE-23 R-1 WD-20 3111CORE-23 R-1 WD-21 3112 CORE-23 R-1 WD-22 3113 CORE-23 R-1 WD-23 3114CORE-23 R-1 WD-24 3115 CORE-23 R-1 WD-25 3116 CORE-23 R-2 WD-11 3117CORE-23 R-2 WD-12 3118 CORE-23 R-2 WD-13 3119 CORE-23 R-2 WD-14 3120CORE-23 R-2 WD-15 3121 CORE-23 R-2 WD-16 3122 CORE-23 R-2 WD-17 3123CORE-23 R-2 WD-18 3124 CORE-23 R-2 WD-19 3125 CORE-23 R-2 WD-20 3126CORE-23 R-2 WD-21 3127 CORE-23 R-2 WD-22 3128 CORE-23 R-2 WD-23 3129CORE-23 R-2 WD-24 3130 CORE-23 R-2 WD-25 3131 CORE-23 R-3 WD-11 3132CORE-23 R-3 WD-12 3133 CORE-23 R-3 WD-13 3134 CORE-23 R-3 WD-14 3135CORE-23 R-3 WD-15 3136 CORE-23 R-3 WD-16 3137 CORE-23 R-3 WD-17 3138CORE-23 R-3 WD-18 3139 CORE-23 R-3 WD-19 3140 CORE-23 R-3 WD-20 3141CORE-23 R-3 WD-21 3142 CORE-23 R-3 WD-22 3143 CORE-23 R-3 WD-23 3144CORE-23 R-3 WD-24 3145 CORE-23 R-3 WD-25 3146 CORE-23 R-4 WD-11 3147CORE-23 R-4 WD-12 3148 CORE-23 R-4 WD-13 3149 CORE-23 R-4 WD-14 3150CORE-23 R-4 WD-15 3151 CORE-23 R-4 WD-16 3152 CORE-23 R-4 WD-17 3153CORE-23 R-4 WD-18 3154 CORE-23 R-4 WD-19 3155 CORE-23 R-4 WD-20 3156CORE-23 R-4 WD-21 3157 CORE-23 R-4 WD-22 3158 CORE-23 R-4 WD-23 3159CORE-23 R-4 WD-24 3160 CORE-23 R-4 WD-25 3161 CORE-23 R-5 WD-11 3162CORE-23 R-5 WD-12 3163 CORE-23 R-5 WD-13 3164 CORE-23 R-5 WD-14 3165CORE-23 R-5 WD-15 3166 CORE-23 R-5 WD-16 3167 CORE-23 R-5 WD-17 3168CORE-23 R-5 WD-18 3169 CORE-23 R-5 WD-19 3170 CORE-23 R-5 WD-20 3171CORE-23 R-5 WD-21 3172 CORE-23 R-5 WD-22 3173 CORE-23 R-5 WD-23 3174CORE-23 R-5 WD-24 3175 CORE-23 R-5 WD-25 3176 CORE-24 R-1 WD-11 3177CORE-24 R-1 WD-12 3178 CORE-24 R-1 WD-13 3179 CORE-24 R-1 WD-14 3180CORE-24 R-1 WD-15 3181 CORE-24 R-1 WD-16 3182 CORE-24 R-1 WD-17 3183CORE-24 R-1 WD-18 3184 CORE-24 R-1 WD-19 3185 CORE-24 R-1 WD-20 3186CORE-24 R-1 WD-21 3187 CORE-24 R-1 WD-22 3188 CORE-24 R-1 WD-23 3189CORE-24 R-1 WD-24 3190 CORE-24 R-1 WD-25 3191 CORE-24 R-2 WD-11 3192CORE-24 R-2 WD-12 3193 CORE-24 R-2 WD-13 3194 CORE-24 R-2 WD-14 3195CORE-24 R-2 WD-15 3196 CORE-24 R-2 WD-16 3197 CORE-24 R-2 WD-17 3198CORE-24 R-2 WD-18 3199 CORE-24 R-2 WD-19 3200 CORE-24 R-2 WD-20 3201CORE-24 R-2 WD-21 3202 CORE-24 R-2 WD-22 3203 CORE-24 R-2 WD-23 3204CORE-24 R-2 WD-24 3205 CORE-24 R-2 WD-25 3206 CORE-24 R-3 WD-11 3207CORE-24 R-3 WD-12 3208 CORE-24 R-3 WD-13 3209 CORE-24 R-3 WD-14 3210CORE-24 R-3 WD-15 3211 CORE-24 R-3 WD-16 3212 CORE-24 R-3 WD-17 3213CORE-24 R-3 WD-18 3214 CORE-24 R-3 WD-19 3215 CORE-24 R-3 WD-20 3216CORE-24 R-3 WD-21 3217 CORE-24 R-3 WD-22 3218 CORE-24 R-3 WD-23 3219CORE-24 R-3 WD-24 3220 CORE-24 R-3 WD-25 3221 CORE-24 R-4 WD-11 3222CORE-24 R-4 WD-12 3223 CORE-24 R-4 WD-13 3224 CORE-24 R-4 WD-14 3225CORE-24 R-4 WD-15 3226 CORE-24 R-4 WD-16 3227 CORE-24 R-4 WD-17 3228CORE-24 R-4 WD-18 3229 CORE-24 R-4 WD-19 3230 CORE-24 R-4 WD-20 3231CORE-24 R-4 WD-21 3232 CORE-24 R-4 WD-22 3233 CORE-24 R-4 WD-23 3234CORE-24 R-4 WD-24 3235 CORE-24 R-4 WD-25 3236 CORE-24 R-5 WD-11 3237CORE-24 R-5 WD-12 3238 CORE-24 R-5 WD-13 3239 CORE-24 R-5 WD-14 3240CORE-24 R-5 WD-15 3241 CORE-24 R-5 WD-16 3242 CORE-24 R-5 WD-17 3243CORE-24 R-5 WD-18 3244 CORE-24 R-5 WD-19 3245 CORE-24 R-5 WD-20 3246CORE-24 R-5 WD-21 3247 CORE-24 R-5 WD-22 3248 CORE-24 R-5 WD-23 3249CORE-24 R-5 WD-24 3250 CORE-24 R-5 WD-25 3251 CORE-25 R-1 WD-11 3252CORE-25 R-1 WD-12 3253 CORE-25 R-1 WD-13 3254 CORE-25 R-1 WD-14 3255CORE-25 R-1 WD-15 3256 CORE-25 R-1 WD-16 3257 CORE-25 R-1 WD-17 3258CORE-25 R-1 WD-18 3259 CORE-25 R-1 WD-19 3260 CORE-25 R-1 WD-20 3261CORE-25 R-1 WD-21 3262 CORE-25 R-1 WD-22 3263 CORE-25 R-1 WD-23 3264CORE-25 R-1 WD-24 3265 CORE-25 R-1 WD-25 3266 CORE-25 R-2 WD-11 3267CORE-25 R-2 WD-12 3268 CORE-25 R-2 WD-13 3269 CORE-25 R-2 WD-14 3270CORE-25 R-2 WD-15 3271 CORE-25 R-2 WD-16 3272 CORE-25 R-2 WD-17 3273CORE-25 R-2 WD-18 3274 CORE-25 R-2 WD-19 3275 CORE-25 R-2 WD-20 3276CORE-25 R-2 WD-21 3277 CORE-25 R-2 WD-22 3278 CORE-25 R-2 WD-23 3279CORE-25 R-2 WD-24 3280 CORE-25 R-2 WD-25 3281 CORE-25 R-3 WD-11 3282CORE-25 R-3 WD-12 3283 CORE-25 R-3 WD-13 3284 CORE-25 R-3 WD-14 3285CORE-25 R-3 WD-15 3286 CORE-25 R-3 WD-16 3287 CORE-25 R-3 WD-17 3288CORE-25 R-3 WD-18 3289 CORE-25 R-3 WD-19 3290 CORE-25 R-3 WD-20 3291CORE-25 R-3 WD-21 3292 CORE-25 R-3 WD-22 3293 CORE-25 R-3 WD-23 3294CORE-25 R-3 WD-24 3295 CORE-25 R-3 WD-25 3296 CORE-25 R-4 WD-11 3297CORE-25 R-4 WD-12 3298 CORE-25 R-4 WD-13 3299 CORE-25 R-4 WD-14 3300CORE-25 R-4 WD-15 3301 CORE-25 R-4 WD-16 3302 CORE-25 R-4 WD-17 3303CORE-25 R-4 WD-18 3304 CORE-25 R-4 WD-19 3305 CORE-25 R-4 WD-20 3306CORE-25 R-4 WD-21 3307 CORE-25 R-4 WD-22 3308 CORE-25 R-4 WD-23 3309CORE-25 R-4 WD-24 3310 CORE-25 R-4 WD-25 3311 CORE-25 R-5 WD-11 3312CORE-25 R-5 WD-12 3313 CORE-25 R-5 WD-13 3314 CORE-25 R-5 WD-14 3315CORE-25 R-5 WD-15 3316 CORE-25 R-5 WD-16 3317 CORE-25 R-5 WD-17 3318CORE-25 R-5 WD-18 3319 CORE-25 R-5 WD-19 3320 CORE-25 R-5 WD-20 3321CORE-25 R-5 WD-21 3322 CORE-25 R-5 WD-22 3323 CORE-25 R-5 WD-23 3324CORE-25 R-5 WD-24 3325 CORE-25 R-5 WD-25 3326 CORE-26 R-1 WD-11 3327CORE-26 R-1 WD-12 3328 CORE-26 R-1 WD-13 3329 CORE-26 R-1 WD-14 3330CORE-26 R-1 WD-15 3331 CORE-26 R-1 WD-16 3332 CORE-26 R-1 WD-17 3333CORE-26 R-1 WD-18 3334 CORE-26 R-1 WD-19 3335 CORE-26 R-1 WD-20 3336CORE-26 R-1 WD-21 3337 CORE-26 R-1 WD-22 3338 CORE-26 R-1 WD-23 3339CORE-26 R-1 WD-24 3340 CORE-26 R-1 WD-25 3341 CORE-26 R-2 WD-11 3342CORE-26 R-2 WD-12 3343 CORE-26 R-2 WD-13 3344 CORE-26 R-2 WD-14 3345CORE-26 R-2 WD-15 3346 CORE-26 R-2 WD-16 3347 CORE-26 R-2 WD-17 3348CORE-26 R-2 WD-18 3349 CORE-26 R-2 WD-19 3350 CORE-26 R-2 WD-20 3351CORE-26 R-2 WD-21 3352 CORE-26 R-2 WD-22 3353 CORE-26 R-2 WD-23 3354CORE-26 R-2 WD-24 3355 CORE-26 R-2 WD-25 3356 CORE-26 R-3 WD-11 3357CORE-26 R-3 WD-12 3358 CORE-26 R-3 WD-13 3359 CORE-26 R-3 WD-14 3360CORE-26 R-3 WD-15 3361 CORE-26 R-3 WD-16 3362 CORE-26 R-3 WD-17 3363CORE-26 R-3 WD-18 3364 CORE-26 R-3 WD-19 3365 CORE-26 R-3 WD-20 3366CORE-26 R-3 WD-21 3367 CORE-26 R-3 WD-22 3368 CORE-26 R-3 WD-23 3369CORE-26 R-3 WD-24 3370 CORE-26 R-3 WD-25 3371 CORE-26 R-4 WD-11 3372CORE-26 R-4 WD-12 3373 CORE-26 R-4 WD-13 3374 CORE-26 R-4 WD-14 3375CORE-26 R-4 WD-15 3376 CORE-26 R-4 WD-16 3377 CORE-26 R-4 WD-17 3378CORE-26 R-4 WD-18 3379 CORE-26 R-4 WD-19 3380 CORE-26 R-4 WD-20 3381CORE-26 R-4 WD-21 3382 CORE-26 R-4 WD-22 3383 CORE-26 R-4 WD-23 3384CORE-26 R-4 WD-24 3385 CORE-26 R-4 WD-25 3386 CORE-26 R-5 WD-11 3387CORE-26 R-5 WD-12 3388 CORE-26 R-5 WD-13 3389 CORE-26 R-5 WD-14 3390CORE-26 R-5 WD-15 3391 CORE-26 R-5 WD-16 3392 CORE-26 R-5 WD-17 3393CORE-26 R-5 WD-18 3394 CORE-26 R-5 WD-19 3395 CORE-26 R-5 WD-20 3396CORE-26 R-5 WD-21 3397 CORE-26 R-5 WD-22 3398 CORE-26 R-5 WD-23 3399CORE-26 R-5 WD-24 3400 CORE-26 R-5 WD-25 3401 CORE-27 R-1 WD-11 3402CORE-27 R-1 WD-12 3403 CORE-27 R-1 WD-13 3404 CORE-27 R-1 WD-14 3405CORE-27 R-1 WD-15 3406 CORE-27 R-1 WD-16 3407 CORE-27 R-1 WD-17 3408CORE-27 R-1 WD-18 3409 CORE-27 R-1 WD-19 3410 CORE-27 R-1 WD-20 3411CORE-27 R-1 WD-21 3412 CORE-27 R-1 WD-22 3413 CORE-27 R-1 WD-23 3414CORE-27 R-1 WD-24 3415 CORE-27 R-1 WD-25 3416 CORE-27 R-2 WD-11 3417CORE-27 R-2 WD-12 3418 CORE-27 R-2 WD-13 3419 CORE-27 R-2 WD-14 3420CORE-27 R-2 WD-15 3421 CORE-27 R-2 WD-16 3422 CORE-27 R-2 WD-17 3423CORE-27 R-2 WD-18 3424 CORE-27 R-2 WD-19 3425 CORE-27 R-2 WD-20 3426CORE-27 R-2 WD-21 3427 CORE-27 R-2 WD-22 3428 CORE-27 R-2 WD-23 3429CORE-27 R-2 WD-24 3430 CORE-27 R-2 WD-25 3431 CORE-27 R-3 WD-11 3432CORE-27 R-3 WD-12 3433 CORE-27 R-3 WD-13 3434 CORE-27 R-3 WD-14 3435CORE-27 R-3 WD-15 3436 CORE-27 R-3 WD-16 3437 CORE-27 R-3 WD-17 3438CORE-27 R-3 WD-18 3439 CORE-27 R-3 WD-19 3440 CORE-27 R-3 WD-20 3441CORE-27 R-3 WD-21 3442 CORE-27 R-3 WD-22 3443 CORE-27 R-3 WD-23 3444CORE-27 R-3 WD-24 3445 CORE-27 R-3 WD-25 3446 CORE-27 R-4 WD-11 3447CORE-27 R-4 WD-12 3448 CORE-27 R-4 WD-13 3449 CORE-27 R-4 WD-14 3450CORE-27 R-4 WD-15 3451 CORE-27 R-4 WD-16 3452 CORE-27 R-4 WD-17 3453CORE-27 R-4 WD-18 3454 CORE-27 R-4 WD-19 3455 CORE-27 R-4 WD-20 3456CORE-27 R-4 WD-21 3457 CORE-27 R-4 WD-22 3458 CORE-27 R-4 WD-23 3459CORE-27 R-4 WD-24 3460 CORE-27 R-4 WD-25 3461 CORE-27 R-5 WD-11 3462CORE-27 R-5 WD-12 3463 CORE-27 R-5 WD-13 3464 CORE-27 R-5 WD-14 3465CORE-27 R-5 WD-15 3466 CORE-27 R-5 WD-16 3467 CORE-27 R-5 WD-17 3468CORE-27 R-5 WD-18 3469 CORE-27 R-5 WD-19 3470 CORE-27 R-5 WD-20 3471CORE-27 R-5 WD-21 3472 CORE-27 R-5 WD-22 3473 CORE-27 R-5 WD-23 3474CORE-27 R-5 WD-24 3475 CORE-27 R-5 WD-25 3476 CORE-28 R-1 WD-11 3477CORE-28 R-1 WD-12 3478 CORE-28 R-1 WD-13 3479 CORE-28 R-1 WD-14 3480CORE-28 R-1 WD-15 3481 CORE-28 R-1 WD-16 3482 CORE-28 R-1 WD-17 3483CORE-28 R-1 WD-18 3484 CORE-28 R-1 WD-19 3485 CORE-28 R-1 WD-20 3486CORE-28 R-1 WD-21 3487 CORE-28 R-1 WD-22 3488 CORE-28 R-1 WD-23 3489CORE-28 R-1 WD-24 3490 CORE-28 R-1 WD-25 3491 CORE-28 R-2 WD-11 3492CORE-28 R-2 WD-12 3493 CORE-28 R-2 WD-13 3494 CORE-28 R-2 WD-14 3495CORE-28 R-2 WD-15 3496 CORE-28 R-2 WD-16 3497 CORE-28 R-2 WD-17 3498CORE-28 R-2 WD-18 3499 CORE-28 R-2 WD-19 3500 CORE-28 R-2 WD-20 3501CORE-28 R-2 WD-21 3502 CORE-28 R-2 WD-22 3503 CORE-28 R-2 WD-23 3504CORE-28 R-2 WD-24 3505 CORE-28 R-2 WD-25 3506 CORE-28 R-3 WD-11 3507CORE-28 R-3 WD-12 3508 CORE-28 R-3 WD-13 3509 CORE-28 R-3 WD-14 3510CORE-28 R-3 WD-15 3511 CORE-28 R-3 WD-16 3512 CORE-28 R-3 WD-17 3513CORE-28 R-3 WD-18 3514 CORE-28 R-3 WD-19 3515 CORE-28 R-3 WD-20 3516CORE-28 R-3 WD-21 3517 CORE-28 R-3 WD-22 3518 CORE-28 R-3 WD-23 3519CORE-28 R-3 WD-24 3520 CORE-28 R-3 WD-25 3521 CORE-28 R-4 WD-11 3522CORE-28 R-4 WD-12 3523 CORE-28 R-4 WD-13 3524 CORE-28 R-4 WD-14 3525CORE-28 R-4 WD-15 3526 CORE-28 R-4 WD-16 3527 CORE-28 R-4 WD-17 3528CORE-28 R-4 WD-18 3529 CORE-28 R-4 WD-19 3530 CORE-28 R-4 WD-20 3531CORE-28 R-4 WD-21 3532 CORE-28 R-4 WD-22 3533 CORE-28 R-4 WD-23 3534CORE-28 R-4 WD-24 3535 CORE-28 R-4 WD-25 3536 CORE-28 R-5 WD-11 3537CORE-28 R-5 WD-12 3538 CORE-28 R-5 WD-13 3539 CORE-28 R-5 WD-14 3540CORE-28 R-5 WD-15 3541 CORE-28 R-5 WD-16 3542 CORE-28 R-5 WD-17 3543CORE-28 R-5 WD-18 3544 CORE-28 R-5 WD-19 3545 CORE-28 R-5 WD-20 3546CORE-28 R-5 WD-21 3547 CORE-28 R-5 WD-22 3548 CORE-28 R-5 WD-23 3549CORE-28 R-5 WD-24 3550 CORE-28 R-5 WD-25 3551 CORE-29 R-1 WD-11 3552CORE-29 R-1 WD-12 3553 CORE-29 R-1 WD-13 3554 CORE-29 R-1 WD-14 3555CORE-29 R-1 WD-15 3556 CORE-29 R-1 WD-16 3557 CORE-29 R-1 WD-17 3558CORE-29 R-1 WD-18 3559 CORE-29 R-1 WD-19 3560 CORE-29 R-1 WD-20 3561CORE-29 R-1 WD-21 3562 CORE-29 R-1 WD-22 3563 CORE-29 R-1 WD-23 3564CORE-29 R-1 WD-24 3565 CORE-29 R-1 WD-25 3566 CORE-29 R-2 WD-11 3567CORE-29 R-2 WD-12 3568 CORE-29 R-2 WD-13 3569 CORE-29 R-2 WD-14 3570CORE-29 R-2 WD-15 3571 CORE-29 R-2 WD-16 3572 CORE-29 R-2 WD-17 3573CORE-29 R-2 WD-18 3574 CORE-29 R-2 WD-19 3575 CORE-29 R-2 WD-20 3576CORE-29 R-2 WD-21 3577 CORE-29 R-2 WD-22 3578 CORE-29 R-2 WD-23 3579CORE-29 R-2 WD-24 3580 CORE-29 R-2 WD-25 3581 CORE-29 R-3 WD-11 3582CORE-29 R-3 WD-12 3583 CORE-29 R-3 WD-13 3584 CORE-29 R-3 WD-14 3585CORE-29 R-3 WD-15 3586 CORE-29 R-3 WD-16 3587 CORE-29 R-3 WD-17 3588CORE-29 R-3 WD-18 3589 CORE-29 R-3 WD-19 3590 CORE-29 R-3 WD-20 3591CORE-29 R-3 WD-21 3592 CORE-29 R-3 WD-22 3593 CORE-29 R-3 WD-23 3594CORE-29 R-3 WD-24 3595 CORE-29 R-3 WD-25 3596 CORE-29 R-4 WD-11 3597CORE-29 R-4 WD-12 3598 CORE-29 R-4 WD-13 3599 CORE-29 R-4 WD-14 3600CORE-29 R-4 WD-15 3601 CORE-29 R-4 WD-16 3602 CORE-29 R-4 WD-17 3603CORE-29 R-4 WD-18 3604 CORE-29 R-4 WD-19 3605 CORE-29 R-4 WD-20 3606CORE-29 R-4 WD-21 3607 CORE-29 R-4 WD-22 3608 CORE-29 R-4 WD-23 3609CORE-29 R-4 WD-24 3610 CORE-29 R-4 WD-25 3611 CORE-29 R-5 WD-11 3612CORE-29 R-5 WD-12 3613 CORE-29 R-5 WD-13 3614 CORE-29 R-5 WD-14 3615CORE-29 R-5 WD-15 3616 CORE-29 R-5 WD-16 3617 CORE-29 R-5 WD-17 3618CORE-29 R-5 WD-18 3619 CORE-29 R-5 WD-19 3620 CORE-29 R-5 WD-20 3621CORE-29 R-5 WD-21 3622 CORE-29 R-5 WD-22 3623 CORE-29 R-5 WD-23 3624CORE-29 R-5 WD-24 3625 CORE-29 R-5 WD-25

TABLE 2

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50or a pharmaceutically acceptable form thereof.

TABLE 3

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100or a pharmaceutically acceptable form thereof.

TABLE 4

101

151

201

251

301

351

401

451

501

551

601

651

701

751

801

851

901

951

1001

1051

1101

1151

1201

1251

1301

1351

1401or a pharmaceutically acceptable form thereof.

In one embodiment, the compound is:

or a pharmaceutically acceptable form thereof.

In one embodiment, for each compound in Table 1, Table 2, Table 3, andTable 4, the alkynyl moiety of the structure

is replaced by an alkenyl moiety of the structure

All of the resulted alkenyl compounds are provided herein. In oneembodiment, the alkenyl moiety has a Z-configuration. In one embodiment,the alkenyl moiety has a E-configuration.

In some embodiments, one or more compounds described herein bind to aPI3 kinase (e.g., bind selectively). In some embodiments, one or morecompounds described herein bind selectively to a γ- or δ-subtype of aPI3 kinase In some embodiments, one or more compounds described hereinbind selectively to a γ-subtype of a PI3 kinase In some embodiments, oneor more compounds described herein bind selectively to a δ-subtype of aPI3 kinase

In some embodiments, non-limiting exemplary compounds exhibit one ormore functional characteristics disclosed herein. For example, one ormore compounds provided herein bind specifically to a PI3 kinase In someembodiments, the IC₅₀ of a compound provided herein for p110α, p110β,p110γ, or p110δ is less than about 1 μM, less than about 100 nM, lessthan about 50 nM, less than about 10 nM, less than about 1 nM, less thanabout 0.5 nM, less than about 100 pM, or less than about 50 pM.

In some embodiments, one or more of the compounds provided herein canselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC₅₀ value of about100 nM, about 50 nM, about 10 nM, about 5 nM, about 100 pM, about 10 pM,or about 1 pM, or less, as measured in an in vitro kinase assay.

In some embodiments, one or more of the compounds provided herein canselectively inhibit one or two members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase), such as, PI3-kinase α,PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some aspects, some ofthe compounds provided herein selectively inhibit PI3-kinase δ ascompared to all other type I PI3-kinases. In other aspects, some of thecompounds provided herein selectively inhibit PI3-kinase δ andPI3-kinase γ as compared to the rest of the type I PI3-kinases. In otheraspects, some of the compounds provided herein selectively inhibitPI3-kinase γ as compared to all other type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC₅₀) with respect to a given type IPI3-kinase, that is at least about 10-fold, at least about 20-fold, atleast about 50-fold, at least about 100-fold, at least about 200-fold,at least about 500-fold, at least about 1000-fold, at least about2000-fold, at least about 5000-fold, or at least about 10,000-fold,lower than the inhibitor's IC₅₀ with respect to the rest of the othertype I PI3-kinases. In one embodiment, an inhibitor selectively inhibitsPI3-kinase δ as compared to PI3-kinase β with at least about 10-foldlower IC₅₀ for PI3-kinase δ. In certain embodiments, the IC₅₀ forPI3-kinase δ is below about 100 nM, while the IC₅₀ for PI3-kinase β isabove about 1000 nM. In certain embodiments, the IC₅₀ for PI3-kinase δis below about 50 nM, while the IC₅₀ for PI3-kinase β is above about5000 nM. In certain embodiments, the IC₅₀ for PI3-kinase δ is belowabout 10 nM, while the IC₅₀ for PI3-kinase β is above about 1000 nM,above about 5,000 nM, or above about 10,000 nM. In one embodiment, aninhibitor selectively inhibits PI3-kinase γ as compared to PI3-kinase βwith at least about 10-fold lower IC₅₀ for PI3-kinase γ. In certainembodiments, the IC₅₀ for PI3-kinase γ is below about 100 nM, while theIC₅₀ for PI3-kinase β is above about 1000 nM. In certain embodiments,the IC₅₀ for PI3-kinase γ is below about 50 nM, while the IC₅₀ forPI3-kinase β is above about 5000 nM. In certain embodiments, the IC₅₀for PI3-kinase γ is below about 10 nM, while the IC₅₀ for PI3-kinase βis above about 1000 nM, above about 5,000 nM, or above about 10,000 nM.

Pharmaceutical Compositions

In some embodiments, provided herein are pharmaceutical compositionscomprising a compound as disclosed herein, or an enantiomer, a mixtureof enantiomers, or a mixture of two or more diastereomers thereof, or apharmaceutically acceptable form thereof (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives), and a pharmaceutically acceptableexcipient, diluent, or carrier, including inert solid diluents andfillers, sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants. In some embodiments, apharmaceutical composition described herein includes a second activeagent such as an additional therapeutic agent, (e.g., achemotherapeutic).

1. Formulations

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can beemployed in pharmaceutical compositions include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol, and the like),and suitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form can be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound described herein and/or thechemotherapeutic with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound as disclosed herein withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Twelfth Edition, McGraw Hill, 2011; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins , 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety. Exceptinsofar as any conventional excipient medium is incompatible with thecompounds provided herein, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutically acceptable composition,the excipient's use is contemplated to be within the scope of thisdisclosure.

In some embodiments, the concentration of one or more of the compoundsprovided in the disclosed pharmaceutical compositions is less than about100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%,about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%,about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%,about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001%, w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is greater than about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%,about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%,about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%,about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%,about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%,about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%,about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%,about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%,about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001%, w/w, w/v,or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.0001% toapproximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%, orapproximately Moto approximately 10%, w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, or approximately 0.1% to approximately 0.9%, w/w, w/vor v/v.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is equal to or less than about 10 g, about 9.5 g, about9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g,about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g,about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g,about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g,about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g,about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g,about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about0.0001 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is more than about 0.0001 g, about 0.0002 g, about0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g,about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g,about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g,about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g,about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g,about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g,about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g,about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is in the range of about 0.0001 to about 10 g, about0.0005 to about 9 g, about 0.001 to about 8 g, about 0.005 to about 7 g,about 0.01 to about 6 g, about 0.05 to about 5 g, about 0.1 to about 4g, about 0.5 to about 4 g, or about 1 to about 3 g.

1A. Formulations for Oral Administration

In some embodiments, provided herein are pharmaceutical compositions fororal administration containing a compound as disclosed herein, and apharmaceutical excipient suitable for oral administration. In someembodiments, provided herein are pharmaceutical compositions for oraladministration containing: (i) an effective amount of a disclosedcompound; optionally (ii) an effective amount of one or more secondagents; and (iii) one or more pharmaceutical excipients suitable fororal administration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more ingredients. In general, the pharmaceuticalcompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the pharmaceutical compositions for an oral dosage form, anyof the usual pharmaceutical media can be employed as carriers, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with the solid oralpreparations. In some embodiments, tablets can be coated by standardaqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants can be used in the pharmaceutical compositions as providedherein to provide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant can produce tablets which candisintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration, and can be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, canbe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein can be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, forexample, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of atleast about 10, while suitable lipophilic surfactants can generally havean HLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants can be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants can include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids, and sterols; polyoxyethylene sterols, derivatives, and analoguesthereof; polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids and sterols; oil-soluble vitamins/vitamin derivatives; andmixtures thereof. Within this group, non-limiting examples of lipophilicsurfactants include glycerol fatty acid esters, propylene glycol fattyacid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member ofvegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound as provided herein and to minimize precipitation of thecompound. This can be especially important for pharmaceuticalcompositions for non-oral use, e.g., pharmaceutical compositions forinjection. A solubilizer can also be added to increase the solubility ofthe hydrophilic drug and/or other components, such as surfactants, or tomaintain the pharmaceutical composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In someembodiments, solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer can be limited to abioacceptable amount, which can be readily determined by one of skill inthe art. In some circumstances, it can be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the pharmaceutical composition toa subject using conventional techniques, such as distillation orevaporation. Thus, if present, the solubilizer can be in a weight ratioof about 10%, 25%, 50%, 100%, or up to about 200% by weight, based onthe combined weight of the drug, and other excipients. If desired, verysmall amounts of solubilizer can also be used, such as about 5%, 2%, 1%or even less. Typically, the solubilizer can be present in an amount ofabout 1% to about 100%, more typically about 5% to about 25% by weight.

The pharmaceutical composition can further include one or morepharmaceutically acceptable additives and excipients. Such additives andexcipients include, without limitation, detackifiers, anti-foamingagents, buffering agents, polymers, antioxidants, preservatives,chelating agents, viscomodulators, tonicifiers, flavorants, colorants,oils, odorants, opacifiers, suspending agents, binders, fillers,plasticizers, lubricants, and mixtures thereof.

Exemplary preservatives can include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. Exemplaryantioxidants include, but are not limited to, alpha tocopherol, ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, monothioglycerol, potassium metabisulfite, propionicacid, propyl gallate, sodium ascorbate, sodium bisulfite, sodiummetabisulfite, and sodium sulfite. Exemplary chelating agents includeethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid, and trisodiumedetate. Exemplary antimicrobial preservatives include, but are notlimited to, benzalkonium chloride, benzethonium chloride, benzylalcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.Exemplary antifungal preservatives include, but are not limited to,butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoicacid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, and sothic acid. Exemplary alcoholpreservatives include, but are not limited to, ethanol, polyethyleneglycol, phenol, phenolic compounds, bisphenol, chlorobutanol,hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid. Other preservatives include, but arenot limited to, tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES), sodium bisulfite, sodium metabisulfite, potassiumsulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben,Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certainembodiments, the preservative is an anti-oxidant. In other embodiments,the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof.

In addition, an acid or a base can be incorporated into thepharmaceutical composition to facilitate processing, to enhancestability, or for other reasons. Examples of pharmaceutically acceptablebases include amino acids, amino acid esters, ammonium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesiumaluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite,magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine,trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.Also suitable are bases that are salts of a pharmaceutically acceptableacid, such as acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonicacid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearicacid, succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid, uric acid, and the like. Salts of polyproticacids, such as sodium phosphate, disodium hydrogen phosphate, and sodiumdihydrogen phosphate can also be used. When the base is a salt, thecation can be any convenient and pharmaceutically acceptable cation,such as ammonium, alkali metals, alkaline earth metals, and the like.Examples can include, but not limited to, sodium, potassium, lithium,magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

1B. Formulations for Parenteral Administration

In some embodiments, provided herein are pharmaceutical compositions forparenteral administration containing a compound as disclosed herein, anda pharmaceutical excipient suitable for parenteral administration. Insome embodiments, provided herein are pharmaceutical compositions forparenteral administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor parenteral administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

The forms in which the disclosed pharmaceutical compositions can beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound asdisclosed herein in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as appropriate, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the appropriateother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation are vacuum-drying and freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionalingredient from a previously sterile-filtered solution thereof.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. Injectable compositions can contain from about 0.1to about 5% w/w of a compound as disclosed herein.

1C. Formulations for Topical Administration

In some embodiments, provided herein are pharmaceutical compositions fortopical (e.g., transdermal) administration containing a compound asdisclosed herein, and a pharmaceutical excipient suitable for topicaladministration. In some embodiments, provided herein are pharmaceuticalcompositions for topical administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for topical administration. In some embodiments, thepharmaceutical composition further contains: (iv) an effective amount ofa third agent.

Pharmaceutical compositions provided herein can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationcan provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the disclosed methods employstransdermal delivery devices (“patches”). Such transdermal patches canbe used to provide continuous or discontinuous infusion of a compound asprovided herein in controlled amounts, either with or without anotheragent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquid jet injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) of a compound provided herein relative tothe total weight of the formulation, although the concentration of thecompound provided herein in the formulation can be as high as thesolubility limit of the compound in the solvent. In some embodiments,topically-administrable formulations can, for example, comprise fromabout 1% to about 9% (w/w) of a compound provided herein, such as fromabout 1% to about 8% (w/w), further such as from about 1% to about 7%(w/w), further such as from about 1% to about 6% (w/w), further such asfrom about 1% to about 5% (w/w), further such as from about 1% to about4% (w/w), further such as from about 1% to about 3% (w/w), and furthersuch as from about 1% to about 2% (w/w) of a compound provided herein.Formulations for topical administration can further comprise one or moreof the additional pharmaceutically acceptable excipients describedherein.

1D. Formulations for Inhalation Administration

In some embodiments, provided herein are pharmaceutical compositions forinhalation administration containing a compound as disclosed herein, anda pharmaceutical excipient suitable for topical administration. In someembodiments, provided herein are pharmaceutical compositions forinhalation administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor inhalation administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

Pharmaceutical compositions for inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidpharmaceutical compositions can contain suitable pharmaceuticallyacceptable excipients as described herein. In some embodiments, thepharmaceutical compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Pharmaceuticalcompositions in pharmaceutically acceptable solvents can be nebulized byuse of inert gases. Nebulized solutions can be inhaled directly from thenebulizing device or the nebulizing device can be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder pharmaceutical compositions can beadministered, e.g., orally or nasally, from devices that deliver theformulation in an appropriate manner.

1E. Formulations for Ocular Administration

In some embodiments, the disclosure provides a pharmaceuticalcomposition for treating ophthalmic disorders. The pharmaceuticalcomposition can contain an effective amount of a compound as disclosedherein and a pharmaceutical excipient suitable for ocularadministration. Pharmaceutical compositions suitable for ocularadministration can be presented as discrete dosage forms, such as dropsor sprays each containing a predetermined amount of an active ingredienta solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Otheradministration forms include intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds as disclosed herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye can be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration can be feasible including, but notlimited to intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in asterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles can be chosen, as is known in the art,including, but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. In some embodiments,additives ordinarily used in the eye drops can be added. Such additivesinclude isotonizing agents (e.g., sodium chloride, etc.), buffer agent(e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogenphosphate, etc.), preservatives (e.g., benzalkonium chloride,benzethonium chloride, chlorobutanol, etc.), thickeners (e.g.,saccharide such as lactose, mannitol, maltose, etc.; e.g., hyaluronicacid or its salt such as sodium hyaluronate, potassium hyaluronate,etc.; e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g.,sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents known to those skilled in theart).

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quarternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases, the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, myristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

1F. Formulations for Controlled Release Administration

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a compound as disclosedherein, and a pharmaceutical excipient suitable for controlled releaseadministration. In some embodiments, provided herein are pharmaceuticalcompositions for controlled release administration containing: (i) aneffective amount of a disclosed compound; optionally (ii) an effectiveamount of one or more second agents; and (iii) one or morepharmaceutical excipients suitable for controlled releaseadministration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

Active agents such as the compounds provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970;6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each ofwhich is incorporated herein by reference. Such dosage forms can be usedto provide slow or controlled release of one or more active agentsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. Thus, the pharmaceuticalcompositions provided encompass single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the disease, disorder, orcondition in a minimum amount of time. Advantages of controlled releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased subject compliance. In addition, controlledrelease formulations can be used to affect the time of onset of actionor other characteristics, such as blood levels of the drug, and can thusaffect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound as disclosed herein thatpromptly produces the desired therapeutic effect, and gradually andcontinually release other amounts of the compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In order to maintain this constant level of the compound in the body,the compound should be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active agent can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used. In yet another embodiment, a controlled releasesystem can be placed in a subject at an appropriate site determined by apractitioner of skill, e.g., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

2. Dosage

A compound described herein can be delivered in the form ofpharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds describedherein and/or one or more additional therapeutic agents such as achemotherapeutic, formulated together with one or more pharmaceuticallyacceptable excipients. In some instances, the compound described hereinand the additional therapeutic agent are administered in separatepharmaceutical compositions and can (e.g., because of different physicaland/or chemical characteristics) be administered by different routes(e.g., one therapeutic is administered orally, while the other isadministered intravenously). In other instances, the compound describedherein and the additional therapeutic agent can be administeredseparately, but via the same route (e.g., both orally or bothintravenously). In still other instances, the compound described hereinand the additional therapeutic agent can be administered in the samepharmaceutical composition.

The selected dosage level will depend upon a variety of factorsincluding, for example, the activity of the particular compoundemployed, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

In general, a suitable daily dose of a compound described herein and/ora chemotherapeutic will be that amount of the compound which, in someembodiments, can be the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed herein. Generally, doses of the compounds described herein fora patient, when used for the indicated effects, will range from about0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg perday, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about100 mg per day, or about 0.0001 mg to about 500 mg per day, or about0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg perday, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg per day. Anexemplary dosage is about 10 to 30 mg per day. In some embodiments, fora 70 kg human, a suitable dose would be about 0.05 to about 7 g/day,such as about 0.05 to about 2.5 g/day. Actual dosage levels of theactive ingredients in the pharmaceutical compositions described hereincan be varied so as to obtain an amount of the active ingredient whichis effective to achieve the desired therapeutic response for aparticular patient, composition, and mode of administration, withoutbeing toxic to the patient. In some instances, dosage levels below thelower limit of the aforesaid range can be more than adequate, while inother cases still larger doses can be employed without causing anyharmful side effect, e.g., by dividing such larger doses into severalsmall doses for administration throughout the day.

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, or bi-weekly. Thedosing schedule can include a “drug holiday,” e.g., the drug can beadministered for two weeks on, one week off, or three weeks on, one weekoff, or four weeks on, one week off, etc., or continuously, without adrug holiday. The compounds can be administered orally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intranasally, sublingually, or by any other route.

In some embodiments, a compound as provided herein is administered inmultiple doses. Dosing can be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing canbe about once a month, about once every two weeks, about once a week, orabout once every other day. In another embodiment, a compound asdisclosed herein and another agent are administered together from aboutonce per day to about 6 times per day. In another embodiment, theadministration of a compound as provided herein and an agent continuesfor less than about 7 days. In yet another embodiment, theadministration continues for more than about 6 days, about 10 days,about 14 days, about 28 days, about two months, about six months, orabout one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

Administration of the pharmaceutical compositions as disclosed hereincan continue as long as necessary. In some embodiments, an agent asdisclosed herein is administered for more than about 1, about 2, about3, about 4, about 5, about 6, about 7, about 14, or about 28 days. Insome embodiments, an agent as disclosed herein is administered for lessthan about 28, about 14, about 7, about 6, about 5, about 4, about 3,about 2, or about 1 day. In some embodiments, an agent as disclosedherein is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

Since the compounds described herein can be administered in combinationwith other treatments (such as additional chemotherapeutics, radiationor surgery), the doses of each agent or therapy can be lower than thecorresponding dose for single-agent therapy. The dose for single-agenttherapy can range from, for example, about 0.0001 to about 200 mg, orabout 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1to about 100 mg, or about 1 to about 50 mg per kilogram of body weightper day. In some embodiments, the dose is about 1 mg/kg, about 5 mg/kg,about 7.5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about25 mg/kg, about 50 mg/kg, about 75 mg/kg, or about 100 mg/kg per day. Insome embodiments, the dose is about 1 mg/kg, about 7.5 mg/kg, about 20mg/kg, or about 50 mg/kg per day.

When a compound provided herein, is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound provided herein unit dose forms ofthe agent and the compound provided herein can be adjusted accordingly.

3. Kits

In some embodiments, provided herein are kits. In one embodiment,provided herein is a kit comprising a compound provided herein or apharmaceutical composition provided herein. The kits can include acompound or pharmaceutical composition as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits can also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the pharmaceutical composition, and/orwhich describe dosing, administration, side effects, drug interactions,or other information useful to the health care provider. Suchinformation can be based on the results of various studies, for example,studies using experimental animals involving in vivo models and studiesbased on human clinical trials.

In some embodiments, a memory aid is provided with the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

The kit can further contain another agent. In some embodiments, thecompound as disclosed herein and the agent are provided as separatepharmaceutical compositions in separate containers within the kit. Insome embodiments, the compound as disclosed herein and the agent areprovided as a single pharmaceutical composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and can be includedin the kit. In other embodiments, kits can further comprise devices thatare used to administer the active agents. Examples of such devicesinclude, but are not limited to, syringes, drip bags, patches, andinhalers. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits can also, in some embodiments,be marketed directly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. The strength of the sheet is such that the tablets or capsulescan be removed from the blister pack by manually applying pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Therapeutic Methods

In one embodiment, provided herein is a method of treating or preventinga PI3K mediated disorder in a subject comprising administering aneffective amount of a compound of provided herein or a pharmaceuticalcomposition provided herein to the subject.

Phosphoinositide 3-kinases (PI3Ks) are members of a conserved family oflipid kinases that regulate numerous cell functions, includingproliferation, differentiation, cell survival and metabolism. Severalclasses of PI3Ks exist in mammalian cells, including Class IA subgroup(e.g., PI3K-α, β, δ), which are generally activated by receptor tyrosinekinases (RTKs); Class IB (e.g., PI3K-γ), which is activated by G-proteincoupled receptors (GPCRs), among others. PI3Ks exert their biologicalactivities via a “PI3K-mediated signaling pathway” that includes severalcomponents that directly and/or indirectly transduce a signal triggeredby a PI3K, including the generation of second messengerphophotidylinositol, 3,4,5-triphosphate (PIP3) at the plasma membrane,activation of heterotrimeric G protein signaling, and generation offurther second messengers such as cAMP, DAG, and IP3, all of which leadsto an extensive cascade of protein kinase activation (reviewed inVanhaesebroeck, B. et al. (2001) Annu Rev Biochem. 70:535-602). Forexample, PI3K-δ is activated by cellular receptors through interactionbetween the PI3K regulatory subunit (p85) SH2 domains, or through directinteraction with RAS. PIP3 produced by PI3K activates effector pathwaysdownstream through interaction with plextrin homology (PH) domaincontaining enzymes (e.g., PDK-1 and AKT [PKB]). (Fung-Leung W P. (2011)Cell Signal. 23(4):603-8). Unlike PI3K-δ, PI3K-γ is not associated witha regulatory subunit of the p85 family, but rather with a regulatorysubunit in the p101 family. PI3K-γ is associated with GPCRs, and isresponsible for the very rapid induction of PIP3. PI3K-γ can be alsoactivated by RAS.

In some embodiments, provided herein are methods of modulating a PI3kinase activity (e.g., selectively modulating) by contacting the kinasewith an effective amount of a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein. Modulation can be inhibition (e.g., reduction) or activation(e.g., enhancement) of kinase activity. In some embodiments, providedherein are methods of inhibiting kinase activity by contacting thekinase with an effective amount of a compound as provided herein insolution. In some embodiments, provided herein are methods of inhibitingthe kinase activity by contacting a cell, tissue, organ that express thekinase of interest, with a compound provided herein. In someembodiments, provided herein are methods of inhibiting kinase activityin a subject by administering into the subject an effective amount of acompound as provided herein, or a pharmaceutically acceptable formthereof. In some embodiments, the kinase activity is inhibited (e.g.,reduced) by more than about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%,when contacted with a compound provided herein as compared to the kinaseactivity without such contact. In some embodiments, provided herein aremethods of inhibiting PI3 kinase activity in a subject (includingmammals such as humans) by contacting said subject with an amount of acompound as provided herein sufficient to inhibit or reduce the activityof the PI3 kinase in said subject.

In some embodiments, the kinase is a lipid kinase or a protein kinase Insome embodiments, the kinase is selected from a PI3 kinase includingdifferent isoforms, such as PI3 kinase α, PI3 kinase β, PI3 kinase γ,PI3 kinase δ; DNA-PK; mTOR; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEKreceptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3);Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1;Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor(IR); and IGFR.

As used herein, a “PI3K-mediated disorder” refers to a disease orcondition involving aberrant PI3K-mediated signaling pathway. In oneembodiment, provided herein is a method of treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound as provided herein, or apharmaceutically acceptable form thereof, or a pharmaceuticalcomposition as provided herein. In some embodiments, provided herein isa method of treating a PI3K-δ or PI3K-γ mediated disorder in a subject,the method comprising administering a therapeutically effective amountof a compound as provided herein, or a pharmaceutically acceptable formthereof, or a pharmaceutical composition as provided herein. In someembodiments, provided herein is a method for inhibiting at least one ofPI3K-δ and PI3K-γ, the method comprising contacting a cell expressingPI3K in vitro or in vivo with an effective amount of a compound orcomposition provided herein. PI3Ks have been associated with a widerange of conditions, including immunity, cancer and thrombosis (reviewedin Vanhaesebroeck, B. et al. (2010) Current Topics in Microbiology andImmunology, DOI 10.1007/82_2010_65). For example, Class I PI3Ks,particularly PI3K-γ and PI3K-δ isoforms, are highly expressed inleukocytes and have been associated with adaptive and innate immunity;thus, these PI3Ks are believed to be important mediators in inflammatorydisorders and hematologic malignancies (reviewed in Harris, S J et al.(2009) Curr Opin Investig Drugs 10(11):1151-62); Rommel C. et al. (2007)Nat Rev Immunol 7(3):191-201; Durand C A et al. (2009) J Immunol.183(9):5673-84; Dil N, Marshall A J. (2009) Mol Immunol. 46(10):1970-8;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86).

PI3K-γ is a Class 1B PI3K that associates with the p101 and p84(p87PIKAP) adaptor proteins, and canonically signals through GPCRs.Non-cononical activation through tyrosine kinase receptors and RAS canoccur. Activated PI3K-γ leads to production of PIP3, which serves as adocking site for downstream effector proteins including AKT and BTK,bringing these enzymes to the cell membrane where they may be activated.A scaffolding role for PI3k-γ has been proposed and may contribute tothe activation of the RAS/MEK/ERK pathway. The interaction with the RASpathway explains activities attributed to kinase dead PI3K-γ in cells orin animals PI3K-γ is essential for function of a variety of immune cellsand pathways. Chemokine responses (including IL-8, fMLP, and C5a),leading to neutrophil or monocyte cell migration, is dependent on PI3K-γ(HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide3-Kinase γ in Inflammation,” Science 287:1049-1053 (2000); SASAKI etal., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, andNeutrophil Migration,” Science 287:1040-1046 (2000); LI et al., “Rolesof PLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated SignalTransduction,” Science 287:1046-1049 (2000)). The requirement forPI3K-γ-dependent neutrophil migration is demonstrated by failure ofarthritis development in the K/BXN serum transfer arthritis model inPI3K-γ knockout mice (Randis et al., Eur. J. Immunol., 2008, 38(5),1215-24). Similarly, the mice fail to develop cellular inflammation andairway hyper-responsiveness in the ovalbumin induced asthma model(Takeda et al., J. Allergy Clin. Immunol., 2009; 123, 805-12). PI3K-γdeficient mice also have defects in T-helper cell function. T-cellcytokine production and proliferation in response to activation isreduced, and T helper dependent viral clearance is defective (Sasaki etal., Science, 2000, 287, 1040-46). T cell dependent inflammatory diseasemodels including EAE also do not develop in PI3K-γ deficient mice, andboth the T-cell activation defect and cellular migration defects maycontribute to efficacy in this model (Comerfold, PLOS One, 2012, 7,e45095). The imiquimod psoriasis model has also been used to demonstratethe importance of PI3K-γ in the inflammatory response. Using PI3K-γdeficient mice in this model, the accumulation of γδ T cells in the skinis blocked, as well as dendritic cell maturation and migration (ROLLERet al., “Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3KγReduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-likeDermatitis,” J. Immunol. 189:4612-4620 (2012)). The role of PI3K-γ incellular trafficking can also be demonstrated in oncology models wheretumor inflammation is important for growth and metastasis of cancers. Inthe Lewis Lung Carcinoma model, monocyte activation, migration, anddifferentiation in tumors are defective. This defect results in areduction in tumor growth and extended survival in PI3K-γ deficient mice(Schmid et al., Cancer Cell, 2011, 19, 715-27) or upon treatment withinhibitors that target PI3K-γ. In pancreatic cancer, PI3K-γ can beinappropriately expressed, and in this solid tumor cancer or otherswhere PI3K-γ plays a functional role, inhibition of PI3K-γ can bebeneficial. Inhibition of PI3K-γ shows promise for the treatment ofhematologic malignancies. In a T-ALL model employing a T cell directedknockout of P-Ten, PI3K-δ and PI3K-γ are both essential for theappropriate development of disease, as shown with genetic deletion ofboth genes (Subramaniam et al. Cancer Cell 21, 459-472, 2012). Inaddition, in this TALL model, treatment with a small molecule inhibitorof both kinases leads to extended survival of these mice. In CLL,chemokine networks support a pseudo-follicular microenvironment thatincludes Nurse like cells, stromal cells and T-helper cells. The rolesof PI3K-γ in the normal chemokine signaling and T cell biology suggestthe value of inhibiting this target in CLL (BURGER, “Inhibiting B-CellReceptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr.Mematol. Malig. Rep. 7:26-33 (2012)). Accordingly, PI3K-γ inhibitors aretherapeutically interesting for diseases of the immune system where celltrafficking and T cell or myeloid cell function is important. Inoncology, solid tumors that are dependent on tumor inflammation, ortumors with high levels of PI3K-γ expression, may be targeted. Forhematological cancers a special role for PI3K-γ and PI3K-δ isoforms inTALL and potentially in CLL suggests targeting these PI3Ks in thesediseases.

Without being limited by a particular theory, PI3K-γ has been shown toplay roles in inflammation, arthritis, asthma, allergy, multiplesclerosis (MS), and cancer, among others (e.g., Ruckle et al., NatureRev., Drug Discovery, 2006, 5, 903-18; Schmid et al., “Myeloid cells intumor inflammation,” Vascular Cell, 2012, doi:10.1186/2045-824X-4-14).For example, PI3K-γ functions in multiple signaling pathways involved inleukocyte activation and migration. PI3K-γ has been shown to drivepriming and survival of autoreactive CD4⁺ T cells during experimentalautoimmune encephalomyelitis (EAE), a model for MS. When administeredfrom onset of EAE, a PI3K-γ inhibitor has been shown to cause inhibitionand reversal of clinical disease, and reduction of demyelination andcellular pathology in the CNS (Comerford et al., PLOS One, 2012, 7,e45095). PI3K-γ also regulates thymocyte development, T cell activation,neutrophil migration, and the oxidative burst (Sasaki et al., Science,2000, 287, 1040-46). In addition, it is shown that allergic airwayhyper-responsiveness, inflammation, and remodeling do not develop inPI3K-γ deficient mice (Takeda et al., J. Allergy Clin. Immunol., 2009;123, 805-12). PI3K-γ is shown to be required for chemoattractant-inducedproduction of phosphatidylinositol 3,4,5-trisphosphate and has animportant role in chemoattractant-induced superoxide production andchemotaxis in mouse neutrophils and in production of T cell-independentantigen-specific antibodies composed of the immunoglobulin λ light chain(Li et al., Science, 2000, 287, 1046-49). PI3K-γ is reported to be acrucial signaling molecule required for macrophage accumulation ininflammation (Hirsch et al., Science, 2000, 287, 1049-53). In cancers,pharmacological or genetic blockade of p110γ suppresses inflammation,growth, and metastasis of implanted and spontaneous tumors, suggestingthat PI3K-γ can be an important therapeutic target in oncology (Schmidet al., Cancer Cell, 2011, 19, 715-27). For example, it is shown thatPI3K-γ has a tumor-specific high accumulation in pancreatic ductaladenocarcinoma (PDAC) in human, signifying a role of PI3K-γ inpancreatic cancer (Edling et al., Human Cancer Biology, 2010, 16(2),4928-37).

PI3K-δ has roles in impairments of B-cell signaling and development,antibody production, T-cell function, Th1 and Th2 differentiation, andmast and basophil degranulation. Without being limited by a particulartheory, PI3K-γ has roles in T-cell function, neutrophil and macrophagerecruitment, macrophage activation, neutrophil oxidative burst, anddendritic cell migration. Inhibition of PI3K-δ and/or PI3K-γ isoformscan result in efficacy against inflammation and cancer, e.g., inarthritis, asthma, multiple sclerosis (MS), and tumor models. Forexample, deficiency in PI3K-δ and/or PI3K-γ can result in efficacy inK/BxN arthritis model (Kyburz et al., Springer Semin. Immunopathology,2003, 25, 79-90) or K/BxN serum transfer model of arthritis (Randis etal., Eur. J. Immunol., 2008, 38(5), 1215-24), where it is shown thatrecognition of the immune complexes depends on both PI3K-δ and PI3K-γ,whereas cell migration is dependent on PI3K-γ. Deficiency in PI3K-δ orPI3K-γ can also result in efficacy in murine ovalbumin (OVA) inducedallergic asthma model (Lee et al., FASEB J., 2006, 20, 455-65; Takeda etal., J. Allergy Clin. Immunol., 2009; 123, 805-12), where it is shownthat inhibition of either PI3K-δ or PI3K-γ inhibits ovalbumin inducedlung infiltration and improves airway responsiveness. Deficiency inPI3K-δ or PI3K-γ can also result in efficacy in murine experimentalautoimmune encephalomyelitis (model for MS), where it is shown thatPI3K-γ deletion may provide better efficacy as compared to PI3K-δdeletion (Haylock-Jacob et al., J. Autoimmunity, 2011, 36, 278-87;Comerford et al., PLOS One, 2012, 7, e45095), including reduction inT-cell receptor induced CD4⁺ T cell activation, leukocyte infiltrationand Th1/Th17 responses, and dendritic cell migration (Comerfold, PLOSOne, 2012, 7, e45095). Furthermore, inhibition of PI3K-γ can also resultin decreased tumor inflammation and growth (e.g., Lewis lung carcinomamodel, Schmid et al., Cancer Cell, 2011, 19(6), 715-27). PI3K-γ deletioncombined with PI3K-δ deletion results in increased survival in T-cellacute lymphoblastic leukemia (T-ALL) (Subramaniam et al., Cancer Cell,2012, 21, 459-72). Inhibitors of both PI3K-δ and PI3K-γ are also shownto be efficacious in PTEN-deleted T-ALL cell line (MOLT-4). In theabsence of PTEN phosphatase tumor suppressor function, PI3K-δ or PI3K-γalone can support the development of leukemia, whereas inactivation ofboth isoforms suppresses tumor formation. Thus, inhibitors of PI3K-δand/or PI3K-γ can be useful in treating inflammation, such as arthritis,allergic asthma, and MS; and in treating cancer, for example, due toeffects such as reductions in solid tumor associated inflammation,angiogenesis and tumor progression.

The importance of PI3K-δ in the development and function of B-cells issupported from inhibitor studies and genetic models. PI3K-δ is animportant mediator of B-cell receptor (BCR) signaling, and is upstreamof AKT, calcium flux, PLCγ, MAP kinase, P70S6k, and FOXO3a activation.PI3K-δ is also important in IL4R, S1P, and CXCR5 signaling, and has beenshown to modulate responses to toll-like receptors 4 and 9. Inhibitorsof PI3K-δ have shown the importance of PI3K-δ in B-cell development(Marginal zone and B1 cells), B-cell activation, chemotaxis, migrationand homing to lymphoid tissue, and in the control of immunoglobulinclass switching leading to the production of IgE. Clayton E et al.(2002) J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) Blood107(2):642-50; Okkenhaug K. et al. (2002) Science 297(5583):1031-4;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86).

In T-cells, PI3K-δ has been demonstrated to have a role in T-cellreceptor and cytokine signaling, and is upstream of AKT, PLCγ, andGSK3b. In PI3K-δ deletion or kinase-dead knock-in mice, or in inhibitorstudies, T-cell defects including proliferation, activation, anddifferentiation have been observed, leading to reduced T helper cell 2(TH2) response, memory T-cell specific defects (DTH reduction), defectsin antigen dependent cellular trafficking, and defects inchemotaxis/migration to chemokines (e.g., S1P, CCR7, CD62L). (Garçon F.et al. (2008) Blood 111(3):1464-71; Okkenhaug K et al. (2006). JImmunol. 177(8):5122-8; Soond D R, et al. (2010) Blood 115(11):2203-13;Reif K, (2004). J Immunol. 2004; 173(4):2236-40; Ji H. et al. (2007)Blood 110(8):2940-7; Webb L M, et al. (2005) J Immunol. 175(5):2783-7;Liu D, et al. (2010) J Immunol. 184(6):3098-105; Haylock-Jacobs S, etal. (2011) J Autoimmun. 2011; 36(3-4):278-87; Jarmin S J, et al. (2008)J Clin Invest. 118(3):1154-64).

Numerous publications support roles of PI3K-δ and PI3K-γ in thedifferentiation, maintenance, and activation of immune and malignantcells, as described in more detail herein.

PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocyteswhere they have distinct and non-overlapping roles in immune celldevelopment and function. See, e.g., PURI and GOLD, “Selectiveinhibitors of phosphoinositide 3-kinase delta: modulators of B-cellfunction with potential for treating autoimmune inflammatory disease andB-cell malignancies,” Front. Immunol. 3:256 (2012); BUITENHUIS et al.,“The role of the PI3k-PKB signaling module in regulation ofhematopoiesis,” Cell Cycle 8(4):560-566 (2009); HOELLENRIEGEL andBURGER, “Phosphoinositide 3′-kinase delta: turning off BCR signaling inChronic Lymphocytic Leukemia,” Oncotarget 2(10):737-738 (2011); HIRSCHet al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γin Inflammation,” Science 287:1049-1053 (2000); LI et al., “Roles ofPLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated SignalTransduction,” Science 287:1046-1049 (2000); SASAKI et al., “Function ofPI3Kγ in Thymocyte Development, T Cell Activation, and NeutrophilMigration,” Science 287:1040-1046 (2000); CUSHING et al., “PI3Kδ andPI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med.Chem. 55:8559-8581 (2012); MAXWELL et al., “Attenuation ofphosphoinositide 3-kinase δ signaling restrains autoimmune disease,” J.Autoimmun. 38:381-391 (2012); HAYLOCK-JACOBS et al., “PI3Kδ drives thepathogenesis of experimental autoimmune encephalomyelitis by inhibitingeffector T cell apoptosis and promoting Th17 differentiation,” J.Autoimmun. 36:278-287 (2011); SOOND et al., “PI3K p110δ regulates T-cellcytokine production during primary and secondary immune responses inmice and humans,” Blood 115(11):2203-2213 (2010); ROLLER et al.,“Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ ReducesIL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis,” J.Immunol. 189:4612-4620 (2012); CAMPS et al., “Blockade of PI3Kγsuppresses joint inflammation and damage in mouse models of rheumatoidarthritis,” Nat. Med. 11(9):936-943 (2005). As key enzymes in leukocytesignaling, PI3K-δ and PI3K-γ facilitate normal B-cell, T-cell andmyeloid cell functions including differentiation, activation, andmigration. See, e.g., HOELLENRIEGEL and BURGER, “Phosphoinositide3′-kinase delta: turning off BCR signaling in Chronic LymphocyticLeukemia,” Oncotarget 2(10):737-738 (2011); CUSHING et al., “PI3Kδ andPI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med.Chem. 55:8559-8581 (2012). PI3K-δ or PI3K-γ activity is critical forpreclinical models of autoimmune and inflammatory diseases. See, e.g.,HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide3-Kinase γ in Inflammation,” Science 287:1049-1053 (2000); LI et al.,“Roles of PLC-β2 and β3 and PI3Kγ in Chemoattractant-Mediated SignalTransduction,” Science 287:1046-1049 (2000); SASAKI et al., “Function ofPI3Kγ in Thymocyte Development, T Cell Activation, and NeutrophilMigration,” Science 287:1040-1046 (2000); CUSHING et al., “PI3Kδ andPI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med.Chem. 55:8559-8581 (2012); MAXWELL et al., “Attenuation ofphosphoinositide 3-kinase δ signaling restrains autoimmune disease,” J.Autoimmun. 38:381-391 (2012); HAYLOCK-JACOBS et al., “PI3Kδ drives thepathogenesis of experimental autoimmune encephalomyelitis by inhibitingeffector T cell apoptosis and promoting Th17 differentiation,” J.Autoimmun. 36:278-287 (2011); SOOND et al., “PI3K p110δ regulates T-cellcytokine production during primary and secondary immune responses inmice and humans,” Blood 115(11):2203-2213 (2010); ROLLER et al.,“Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ ReducesIL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis,” J.Immunol. 189:4612-4620 (2012); CAMPS et al., “Blockade of PI3Kγsuppresses joint inflammation and damage in mouse models of rheumatoidarthritis,” Nat. Med. 11(9):936-943 (2005). Given the key role forPI3K-δ and PI3K-γ in immune function, inhibitors of the PI3K-δ and/or γhave therapeutic potential in immune-related inflammatory or neoplasticdiseases.

PI3K-δ and PI3K-γ are central to the growth and survival of B- andT-cell malignancies and inhibition of these isoforms may effectivelylimit these diseases. See, e.g., SUBRAMANIAM et al., “TargetingNonclassical Oncogenes for Therapy in T-ALL,” Cancer Cell 21:459-472(2012); LANNUTTI et al., “CAL-101 a p110δ selectivephosphatidylinositol-3-kinase inhibitor for the treatment of B-cellmalignancies, inhibits PI3K signaling and cellular viability,” Blood117(2):591-594 (2011). PI3K-δ and PI3K-γ support the growth and survivalof certain B-cell malignancies by mediating intracellular BCR signalingand interactions between the tumor cells and their microenvironment.See, e.g., PURI and GOLD, “Selective inhibitors of phosphoinositide3-kinase delta: modulators of B-cell function with potential fortreating autoimmune inflammatory disease and B-cell malignancies,”Front. Immunol. 3:256 (2012); HOELLENRIEGEL et al., “Thephosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cellreceptor signaling and chemokine networks in chronic lymphocyticleuckemia,” Blood 118(13):3603-3612 (2011); BURGER, “Inhibiting B-CellReceptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr.Mematol. Malig. Rep. 7:26-33 (2012). Increased BCR signaling is acentral pathologic mechanism of B-cell malignancies and PI3K activationis a direct consequence of BCR pathway activation. See, e.g., BURGER,“Inhibiting B-Cell Receptor Signaling Pathways in Chronic LymphocyticLeukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012); HERISHANU et al.,“The lymph node microenvironment promotes B-cell receptor signaling,NF-κB activation, and tumor proliferation in chronic lymphocyticleukemia,” Blood 117(2):563-574 (2011); DAVIS et al., “Chronic activeB-cell-receptor signaling in diffuse large B-cell lymphoma,” Nature463:88-92 (2010); PIGHI et al., “Phospho-proteomic analysis of mantlecell lymphoma cells suggests a pro-survival role of B-cell receptorsignaling,” Cell Oncol. (Dordr) 34(2):141-153 (2011); RIZZATTI et al.,“Gene expression profiling of mantle cell lymphoma cells revealsaberrant expression of genes from the PI3K-AKT, WNT and TGFβ signalingpathways,” Brit. J. Haematol. 130:516-526 (2005); MARTINEZ et al., “TheMolecular Signature of Mantle Cell Lymphoma Reveals Multiple SignalsFavoring Cell Survival,” Cancer Res. 63:8226-8232 (2003). Interactionsbetween malignant B-cells and supporting cells (eg, stromal cells,nurse-like cells) in the tumor microenvironment are important for tumorcell survival, proliferation, homing, and tissue retention. See, e.g.,BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in ChronicLymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012);HERISHANU et al., “The lymph node microenvironment promotes B-cellreceptor signaling, NF-κB activation, and tumor proliferation in chroniclymphocytic leukemia,” Blood 117(2):563-574 (2011); KURTOVA et al.,“Diverse marrow stromal cells protect CLL cells from spontaneous anddrug-induced apoptosis: development of a reliable and reproduciblesystem to assess stromal cell adhesion-mediated drug resistance,” Blood114(20): 4441-4450 (2009); BURGER et al., “High-level expression of theT-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cellsin nurselike cell cocultures and after BCR stimulation,” Blood 113(13)3050-3058 (2009); QUIROGA et al., “B-cell antigen receptor signalingenhances chronic lymphocytic leukemia cell migration and survival:specific targeting with a novel spleen tyrosine kinase inhibitor, R406,”Blood 114(5):1029-1037 (2009) Inhibiting PI3K-δ,γ with an inhibitor incertain malignant B-cells can block the BCR-mediated intracellularsurvival signaling as well as key interactions with theirmicroenvironment that are critical for their growth.

PI3K-δ and PI3K-γ also play a direct role in the survival andproliferation of certain T-cell malignancies. See, e.g., SUBRAMANIAM etal., “Targeting Nonclassical Oncogenes for Therapy in T-ALL,” CancerCell 21:459-472 (2012). Aberrant PI3K-δ and PI3K-γ activity provides thesignals necessary for the development and growth of certain T-cellmalignancies. While BTK is expressed in B-cells, it is not expressed inT-cells, and therefore BTK is not a viable target for the treatment ofT-cell malignancies. See, e.g., NISITANI et al., “Posttranscriptionalregulation of Bruton's tyrosine kinase expression in antigenreceptor-stimulated splenic B cells,” PNAS 97(6):2737-2742 (2000); DEWEERS et al., “The Bruton's tyrosine kinase gene is expressed throughoutB cell differentiation, from early precursor B cell stages precedingimmunoglobulin gene rearrangement up to mature B cell stages,” Eur. J.Immunol. 23:3109-3114 (1993); SMITH et al., “Expression of Bruton'sAgammaglobulinemia Tyrosine Kinase Gene, BTK, Is SelectivelyDown-Regulated in T Lymphocytes and Plasma. Cells,” J. Immunol.152:557-565 (1994). PI3K-δ and/or γ inhibitors may have uniquetherapeutic potential in T-cell malignancies.

In neutrophils, PI3K-δ, along with PI3K-γ, contribute to the responsesto immune complexes, FCγRII signaling, including migration andneutrophil respiratory burst Human neutrophils undergo rapid inductionof PIP3 in response to formyl peptide receptor (FMLP) or complementcomponent C5a (C5a) in a PI3K-γ dependent manner, followed by a longerPIP3 production period that is PI3K-δ dependent, and is essential forrespiratory burst. The response to immune complexes is contributed byPI3K-δ, PI3K-γ, and PI3K-β, and is an important mediator of tissuedamage in models of autoimmune disease (Randis T M et al. (2008) Eur JImmunol. 38(5):1215-24; Pinho V, (2007) J Immunol. 179(11):7891-8; SadhuC. et al. (2003) J Immunol. 170(5):2647-54 ; Condliffe A M et al. (2005)Blood 106(4):1432-40). It has been reported that in certain autoimmunediseases, preferential activation of PI3K-β may be involved (Kulkarni etal., Immunology (2011) 4(168) ra23: 1-11). It was also reported thatPI3K-β-deficient mice were highly protected in an FcγR-dependent modelof autoantibody-induced skin blistering and partially protected in anFcγR-dependent model of inflammatory arthritis, whereas combineddeficiency of PI3K-β and PI3K-δ resulted in near complete protection ininflammatory arthritis (Id.).

In macrophages collected from patients with chronic obstructivepulmonary disease (COPD), glucocorticoid responsiveness can be restoredby treatment of the cells with inhibitors of PI3K-δ. Macrophages alsorely on PI3K-δ and PI3K-γ for responses to immune complexes through thearthus reaction (FCγR and C5a signaling) (Randis T M, et al. (2008) EurJ Immunol. 38(5):1215-24 ; Marwick J A et al. (2009) Am J Respir CritCare Med. 179(7):542-8; Konrad S, et al. (2008) J Biol Chem.283(48):33296-303).

In mast cells, stem cell factor-(SCF) and IL3-dependent proliferation,differentiation and function are PI3K-δ dependent, as is chemotaxis. Theallergen/IgE crosslinking of FCγR1 resulting in cytokine release anddegranulation of the mast cells is severely inhibited by treatment withPI3K-δ inhibitors, suggesting a role for PI3K-δ in allergic disease (AliK et al. (2004) Nature 431(7011):1007-11; Lee K S, et al. (2006) FASEBJ. 20(3):455-65; Kim M S, et al. (2008) Trends Immunol. 29(10):493-501).

Natural killer (NK) cells are dependent on both PI3K-δ and PI3K-γ forefficient migration towards chemokines including CXCL10, CCL3, S1P andCXCL12, or in response to LPS in the peritoneum (Guo H, et al. (2008) JExp Med. 205(10):2419-35; Tassi I, et al. (2007) Immunity 27(2):214-27;Saudemont A, (2009) Proc Natl Acad Sci USA. 106(14):5795-800; Kim N, etal. (2007) Blood 110(9):3202-8).

The roles of PI3K-δ and PI3K-γ in the differentiation, maintenance, andactivation of immune cells support a role for these enzymes ininflammatory disorders ranging from autoimmune diseases (e.g.,rheumatoid arthritis, multiple sclerosis) to allergic inflammatorydisorders, such as asthma, and inflammatory respiratory disease, such asCOPD. Extensive evidence is available in experimental animal models, orcan be evaluated using art-recognized animal models. In an embodiment,described herein is a method of treating inflammatory disorders rangingfrom autoimmune diseases (e.g., rheumatoid arthritis, multiplesclerosis) to allergic inflammatory disorders, such as asthma and COPDusing a compound described herein.

For example, inhibitors of PI3K-δ and/or -γ have been shown to haveanti-inflammatory activity in several autoimmune animal models forrheumatoid arthritis (Williams, O. et al. (2010) Chem Biol,17(2):123-34; WO 2009/088986; WO2009/088880; WO 2011/008302; eachincorporated herein by reference). PI3K-δ is expressed in the RAsynovial tissue (especially in the synovial lining which containsfibroblast-like synoviocytes (FLS), and selective PI3K-δ inhibitors havebeen shown to be effective in inhibiting synoviocyte growth and survival(Bartok et al. (2010) Arthritis Rheum 62 Suppl 10:362). Several PI3K-δand -γ inhibitors have been shown to ameliorate arthritic symptoms(e.g., swelling of joints, reduction of serum-induced collagen levels,reduction of joint pathology and/or inflammation), in art-recognizedmodels for RA, such as collagen-induced arthritis and adjuvant inducedarthritis (WO 2009/088986; WO2009/088880; WO 2011/008302; eachincorporated herein by reference).

The role of PI3K-δ has also been shown in models of T-cell dependentresponse, including the DTH model. In the murine experimental autoimmuneencephalomyelitis (EAE) model of multiple sclerosis, the PI3K-γ/δ-doublemutant mice are resistant. PI3K-δ inhibitors have also been shown toblock EAE disease induction and development of TH-17 cells both in vitroand in vivo (Haylock-Jacobs, S. et al. (2011) J. Autoimmunity36(3-4):278-87).

Systemic lupus erythematosus (SLE) is a complex disease that atdifferent stages requires memory T-cells, B-cell polyclonal expansionand differentiation into plasma cells, and the innate immune response toendogenous damage associated molecular pattern molecules (DAMPS), andthe inflammatory responses to immune complexes through the complementsystem as well as the F_(C) receptors. The role of PI3K-δ and PI3K-γtogether in these pathways and cell types suggest that blockade with aninhibitor would be effective in these diseases. A role for PI3K in lupusis also predicted by two genetic models of lupus. The deletion ofphosphatase and tensin homolog (PTEN) leads to a lupus-like phenotype,as does a transgenic activation of Class 1A PI3Ks, which includesPI3K-δ. The deletion of PI3K-γ in the transgenically activated class 1Alupus model is protective, and treatment with a PI3K-γ selectiveinhibitor in the murine MLR/lpr model of lupus improves symptoms(Barber, D F et al. (2006) J. Immunol. 176(1): 589-93).

In allergic disease, PI3K-δ has been shown by genetic models and byinhibitor treatment to be essential for mast-cell activation in apassive cutaneous anaphalaxis assay (Ali K et al. (2008) J Immunol.180(4):2538-44; Ali K, (2004) Nature 431(7011):1007-11). In a pulmonarymeasure of response to immune complexes (Arthus reaction) a PI3K-δknockout is resistant, showing a defect in macrophage activation and C5aproduction. Knockout studies and studies with inhibitors for both PI3K-δand PI3K-γ support a role for both of these enzymes in the ovalbumininduced allergic airway inflammation and hyper-responsiveness model (LeeK S et al. (2006) FASEB J. 20(3):455-65). Reductions of infiltration ofeosinophils, neutrophils, and lymphocytes as well as TH2 cytokines (IL4,IL5, and IL13) were seen with both PI3K-δ specific and dual PI3K-δ andPI3K-γ inhibitors in the Ova induced asthma model (Lee K S et al. (2006)J Allergy Clin Immunol 118(2):403-9).

PI3K-δ and PI3K-γ inhibition can be used in treating COPD. In the smokedmouse model of COPD, the PI3K-δ knockout does not develop smoke inducedglucocorticoid resistance, while wild-type and PI3K-γ knockout mice do.An inhaled formulation of dual PI3K-δ and PI3K-γ inhibitor blockedinflammation in a LPS or smoke COPD models as measured by neutrophiliaand glucocorticoid resistance (Doukas J, et al. (2009) J Pharmacol ExpTher. 328(3):758-65).

Class I PI3Ks, particularly PI3K-δ and PI3K-γ isoforms, are alsoassociated with cancers (reviewed, e.g., in Vogt, P K et al. (2010) CurrTop Microbiol Immunol. 347:79-104; Fresno Vara, J A et al. (2004) CancerTreat Rev. 30(2):193-204; Zhao, L and Vogt, P K. (2008) Oncogene27(41):5486-96). Inhibitors of PI3K, e.g., PI3K-δ and/or PI3K-γ, havebeen shown to have anti-cancer activity (e.g., Courtney, K D et al.(2010) J Clin Oncol. 28(6):1075-1083); Markman, B et al. (2010) AnnOncol. 21(4):683-91; Kong, D and Yamori, T (2009) Curr Med Chem.16(22):2839-54; Jimeno, A et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3542); Flinn, I W et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3543); Shapiro, G et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3500); Wagner, A J et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3501); Vogt, P K et al. (2006) Virology 344(1):131-8; Ward, S etal. (2003) Chem Biol. 10(3):207-13; WO 2011/041399; US 2010/0029693; US2010/0305096; US 2010/0305084; each incorporated herein by reference).

In one embodiment, described herein is a method of treating cancer.Types of cancer that can be treated with an inhibitor of PI3K(particularly, PI3K-δ and/or PI3K-γ) include, e.g., leukemia, chroniclymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia(e.g., Salmena, L et al. (2008) Cell 133:403-414; Chapuis, N et al.(2010) Clin Cancer Res. 16(22):5424-35; Khwaja, A (2010) Curr TopMicrobiol Immunol. 347:169-88); lymphoma, e.g., non-Hodgkin's lymphoma(e.g., Salmena, L et al. (2008) Cell 133:403-414); lung cancer, e.g.,non-small cell lung cancer, small cell lung cancer (e.g., Herrera, V Aet al. (2011) Anticancer Res. 31(3):849-54); melanoma (e.g., Haluska, Fet al. (2007) Semin Oncol. 34(6):546-54); prostate cancer (e.g., Sarker,D et al. (2009) Clin Cancer Res. 15(15):4799-805); glioblastoma (e.g.,Chen, J S et al. (2008) Mol Cancer Ther. 7:841-850); endometrial cancer(e.g., Bansal, N et al. (2009) Cancer Control. 16(1):8-13); pancreaticcancer (e.g., Furukawa, T (2008) J Gastroenterol. 43(12):905-11); renalcell carcinoma (e.g., Porta, C and Figlin, R A (2009) J Urol.182(6):2569-77); colorectal cancer (e.g., Saif, M W and Chu, E (2010)Cancer J. 16(3):196-201); breast cancer (e.g., Tothett, N E et al.(2008) Biochem J. 415:97-100); thyroid cancer (e.g., Brzezianska, E andPastuszak-Lewandoska, D (2011) Front Biosci. 16:422-39); and ovariancancer (e.g., Mazzoletti, M and Broggini, M (2010) Curr Med Chem.17(36):4433-47).

Numerous publications support a role of PI3K-δ and PI3K-γ in treatinghematological cancers. PI3K-δ and PI3K-γ are highly expressed in theheme compartment, and solid tumors, including prostate, breast andglioblastomas (Chen J. S. et al. (2008) Mol Cancer Ther. 7(4):841-50;Ikeda H. et al. (2010) Blood 116(9):1460-8).

In hematological cancers including acute myeloid leukemia (AML),multiple myeloma (MM), and chronic lymphocytic leukemia (CLL),overexpression and constitutive activation of PI3K-δ supports the modelthat PI3K-δ inhibition would be therapeutic Billottet C, et al. (2006)Oncogene 25(50):6648-59; Billottet C, et al. (2009) Cancer Res.69(3):1027-36; Meadows, S A, 52^(nd) Annual ASH Meeting and Exposition;2010 Dec. 4-7; Orlando, Fla.; Ikeda H, et al. (2010) Blood116(9):1460-8; Herman S E et al. (2010) Blood 116(12):2078-88; Herman SE et al. (2011). Blood 117(16):4323-7.

In one embodiment, described herein is a method of treatinghematological cancers including, but not limited to acute myeloidleukemia (AML), multiple myeloma (MM), and chronic lymphocytic leukemia(CLL).

A PI3K-δ inhibitor (CAL-101) has been evaluated in a phase 1 trial inpatients with haematological malignancies, and showed activity in CLL inpatients with poor prognostic characteristics. In CLL, inhibition ofPI3K-δ not only affects tumor cells directly, but it also affects theability of the tumor cells to interact with their microenvironment. Thismicroenvironment includes contact with and factors from stromal cells,T-cells, nurse like cells, as well as other tumor cells. CAL-101suppresses the expression of stromal and T-cell derived factorsincluding CCL3, CCL4, and CXCL13, as well as the CLL tumor cells'ability to respond to these factors. CAL-101 treatment in CLL patientsinduces rapid lymph node reduction and redistribution of lymphocytesinto the circulation, and affects tonic survival signals through theBCR, leading to reduced cell viability, and an increase in apoptosis.Single agent CAL-101 treatment was also active in mantle cell lymphomaand refractory non Hodgkin's lymphoma (Furman, R R, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.;Hoellenriegel, J, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010Dec. 4-7; Orlando, Fla.; Webb, H K, et al. 52^(nd) Annual ASH Meetingand Exposition; 2010 Dec. 4-7; Orlando, Fla.; Meadows, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Kahl,B, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010 Dec. 4-7;Orlando, Fla.; Lannutti B J, et al. (2011) Blood 117(2):591-4).

PI3K-δ inhibitors have shown activity against PI3K-δ positive gliomas invitro (Kashishian A, et al. Poster presented at: The AmericanAssociation of Cancer Research 102^(nd) Annual Meeting; 2011 Apr. 2-6;Orlando, Fla.). PI3K-δ is the PI3K isoform that is most commonlyactivated in tumors where the PTEN tumor suppressor is mutated (Ward S,et al. (2003) Chem Biol. 10(3):207-13). In this subset of tumors,treatment with the PI3K-δ inhibitor either alone or in combination witha cytotoxic agent can be effective.

Another mechanism for PI3K-δ inhibitors to have an effect in solidtumors involves the tumor cells' interaction with theirmicro-environment. PI3K-δ, PI3K-γ, and PI3K-β are expressed in theimmune cells that infiltrate tumors, including tumor infiltratinglymphocytes, macrophages, and neutrophils. PI3K-δ inhibitors can modifythe function of these tumor-associated immune cells and how they respondto signals from the stroma, the tumor, and each other, and in this wayaffect tumor cells and metastasis (Hoellenriegel, J, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.).

PI3K-δ is also expressed in endothelial cells. It has been shown thattumors in mice treated with PI3K-δ selective inhibitors are killed morereadily by radiation therapy. In this same study, capillary networkformation is impaired by the PI3K inhibitor, and it is postulated thatthis defect contributes to the greater killing with radiation. PI3K-δinhibitors can affect the way in which tumors interact with theirmicroenvironment, including stromal cells, immune cells, and endothelialcells and be therapeutic either on its own or in conjunction withanother therapy (Meadows, S A, et al. Paper presented at: 52^(nd) AnnualASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Geng L, et al.(2004) Cancer Res. 64(14):4893-9).

In one embodiment, provided herein is a method of treating or preventinga cancer or disease, such as hematologic malignancy, or a specific typeor sub-type of cancer or disease, such as a specific type or sub-type ofhematologic malignancy, with a PI3K-γ selective inhibitor, wherein theadverse effects associated with administration of inhibitors for otherisoform(s) of PI3K (e.g., PI3K-α and/or PI3K-β) are reduced. In oneembodiment, provided herein is a method of treating or preventing acancer or disease, such as hematologic malignancy, or a specific type orsub-type of cancer or disease, such as a specific type or sub-type ofhematologic malignancy, with a PI3K-γ selective inhibitor, at a lower(e.g., by about 10%, by about 20%, by about 30%, by about 40%, by about50%, by about 60%, by about 70%, or by about 80%) dose as compared totreatment with a PI3K-γ non-selective or less selective PI3K-γ inhibitor(e.g., a PI3Kpan inhibitors, e.g., inhibiting PI3K-α, β, δ, and γ).

The role of PI3K-γ pathway in promoting myeloid cell trafficking totumors and the role of blockade of p100γ in suppression of tumorinflammation and growth in breast cancer, pancreatic cancer, and lungcancer are reported, for example, in Schmid et al. (2011) Cancer Cell19, 715-727, the entirety of which is incorporated herein by reference.In one embodiment, provided herein is a method of treating or preventingpancreatic cancer with a PI3K inhibitor. In another embodiment, providedherein is a method of treating or preventing breast cancer with a PI3Kinhibitor. In yet another embodiment, provided herein is a method oftreating or preventing lung cancer with a PI3K inhibitor. In oneembodiment, the PI3K inhibitor is a PI3K-γ inhibitor, selective ornon-selective over one or more other PI3K isoform(s). In one embodiment,the PI3K inhibitor is a PI3K-γ selective inhibitor.

In certain embodiments, provided herein is a method of treating adisorder or disease provided herein, comprising administering a compoundprovided herein, e.g., a PI3K γ selective inhibitor, a PI3K δ selectiveinhibitor, or a PI3K γ/δ dual inhibitor. Without being limited by aparticular theory, in some embodiments, selectively inhibiting PI3K-γisoform can provide a treatment regimen where adverse effects associatedwith administration of a non-selective PI3K inhibitor are minimized orreduced. Without being limited by a particular theory, in someembodiments, selectively inhibiting PI3K-δ isoform can provide atreatment regimen where adverse effects associated with administrationof a non-selective PI3K inhibitor are minimized or reduced. Withoutbeing limited by a particular theory, in some embodiments, selectivelyinhibiting PI3K-δ and γ isoform can provide a treatment regimen whereadverse effects associated with administration of a non-selective PI3Kinhibitor are minimized or reduced. Without being limited by aparticular theory, it is believed that the adverse effects can bereduced by avoiding the inhibition of other isoforms (e.g., α or β) ofPI3K.

In one embodiment, the adverse effect is hyperglycemia. In anotherembodiment, the adverse effect is rash. In another embodiment, theadverse effect is impaired male fertility that may result frominhibition of β isoform of PI3K (see, e.g., Ciraolo et al., MolecularBiology of the Cell, 21: 704-711 (2010)). In another embodiment, theadverse effect is testicular toxicity that may result from inhibition ofPI3K-β (see, e.g., Wisler et al., Amgen SOT, Abstract ID #2334 (2012)).In another embodiment, the adverse effect is embryonic lethality (see,e.g., Bi et al., J Biol Chem, 274: 10963-10968 (1999)). In anotherembodiment, the adverse effect is defective platelet aggregation (see,e.g., Kulkarni et al., Science, 287: 1049-1053 (2000)). In anotherembodiment, the adverse effect is functionally defective neutrophil(id).

In certain embodiments, the PI3K-γ inhibitor selectively modulatesphosphatidyl inositol-3 kinase (PI3 kinase) gamma isoform. In oneembodiment, the PI3K-γ inhibitor selectively inhibits the gamma isoformover the alpha, beta, or delta isoform. In one embodiment, the PI3K-γinhibitor selectively inhibits the gamma isoform over the alpha or betaisoform. In one embodiment, the PI3K-γ inhibitor selectively inhibitsthe gamma isoform over the alpha, beta, and delta isoforms. In oneembodiment, the PI3K-γ inhibitor selectively inhibits the gamma isoformover the alpha and beta isoforms. In one embodiment, the PI3K-γinhibitor selectively inhibits the gamma isoform over the alpha and betaisoforms, but not the delta isoform. By way of non-limiting example, theratio of selectivity can be greater than a factor of about 10, greaterthan a factor of about 50, greater than a factor of about 100, greaterthan a factor of about 200, greater than a factor of about 400, greaterthan a factor of about 600, greater than a factor of about 800, greaterthan a factor of about 1000, greater than a factor of about 1500,greater than a factor of about 2000, greater than a factor of about5000, greater than a factor of about 10,000, or greater than a factor ofabout 20,000, where selectivity can be measured by ratio of IC₅₀ values,among other means. In one embodiment, the selectivity of PI3K gammaisoform over an other PI3K isoform is measured by the ratio of the IC₅₀value against the other PI3K isoform to the IC₅₀ value against PI3Kgamma isoform. In certain embodiments, the PI3 kinase gamma isoform IC₅₀activity of a compound as disclosed herein can be less than about 1000nM, less than about 100 nM, less than about 10 nM, or less than about 1nM. For example, a compound that selectively inhibits one isoform ofPI3K over another isoform of PI3K has an activity of at least 2× againsta first isoform relative to the compound's activity against the secondisoform (e.g., at least about 3×, 5×, 10×, 20×, 50×, 100×, 200×, 500×,or 1000×).

In other embodiments, inhibition of PI3K (such as PI3K-δ and/or PI3K-γ)can be used to treat a neuropsychiatric disorder, e.g., an autoimmunebrain disorder. Infectious and immune factors have been implicated inthe pathogenesis of several neuropsychiatric disorders, including, butnot limited to, Sydenham's chorea (SC) (Garvey, M. A. et al. (2005) J.Child Neurol. 20:424-429), Tourette's syndrome (TS), obsessivecompulsive disorder (OCD) (Asbahr, F. R. et al. (1998) Am. J. Psychiatry155:1122-1124), attention deficit/hyperactivity disorder (AD/HD)(Hirschtritt, M. E. et al. (2008) Child Neuropsychol. 1:1-16; Peterson,B. S. et al. (2000) Arch. Gen. Psychiatry 57:364-372), anorexia nervosa(Sokol, M. S. (2000) J. Child Adolesc. Psychopharmacol. 10:133-145;Sokol, M. S. et al. (2002) Am. J. Psychiatry 159:1430-1432), depression(Leslie, D. L. et al. (2008) J. Am. Acad. Child Adolesc. Psychiatry47:1166-1172), and autism spectrum disorders (ASD) (Hollander, E. et al.(1999) Am. J. Psychiatry 156:317-320; Margutti, P. et al. (2006) Curr.Neurovasc. Res. 3:149-157). A subset of childhood obsessive compulsivedisorders and tic disorders has been grouped as Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococci (PANDAS). PANDASdisorders provide an example of disorders where the onset andexacerbation of neuropsychiatric symptoms is preceded by a streptococcalinfection (Kurlan, R., Kaplan, E. L. (2004) Pediatrics 113:883-886;Garvey, M. A. et al. (1998) J. Clin. Neurol. 13:413-423). Many of thePANDAS disorders share a common mechanism of action resulting fromantibody responses against streptococcal associated epitopes, such asGlcNAc, which produces neurological effects (Kirvan. C. A. et al. (2006)J. Neuroimmunol. 179:173-179). Autoantibodies recognizing centralnervous system (CNS) epitopes are also found in sera of most PANDASsubjects (Yaddanapudi, K. et al. (2010) Mol. Psychiatry 15:712-726).Thus, several neuropsychiatric disorders have been associated withimmune and autoimmune components, making them suitable for therapiesthat include PI3K-δ and/or PI3K-γ inhibition.

In certain embodiments, a method of treating (e.g., reducing orameliorating one or more symptoms of) a neuropsychiatric disorder,(e.g., an autoimmune brain disorder), using a PI3K-δ and/or PI3K-γinhibitor is described, alone or in combination therapy. For example,one or more PI3K-δ and/or PI3K-γ inhibitors described herein can be usedalone or in combination with any suitable therapeutic agent and/ormodalities, e.g., dietary supplement, for treatment of neuropsychiatricdisorders. Exemplary neuropsychiatric disorders that can be treated withthe PI3K-δ and/or PI3K-γ inhibitors described herein include, but arenot limited to, PANDAS disorders, Sydenham's chorea, Tourette'ssyndrome, obsessive compulsive disorder, attention deficit/hyperactivitydisorder, anorexia nervosa, depression, and autism spectrum disorders.Pervasive Developmental Disorder (PDD) is an exemplary class of autismspectrum disorders that includes Autistic Disorder, Asperger's Disorder,Childhood Disintegrative Disorder (CDD), Rett's Disorder and PDD-NotOtherwise Specified (PDD-NOS). Animal models for evaluating the activityof the PI3K-δ and/or PI3K-γ inhibitor are known in the art. For example,a mouse model of PANDAS disorders is described in, e.g., Yaddanapudi, K.et al. (2010) supra; and Hoffman, K. I. et al. (2004) J. Neurosci.24:1780-1791.

In some embodiments, provided herein is a method for treating rheumatoidarthritis or asthma in a subject, or for reducing a rheumatoidarthritis-associated symptom or an asthma-associated symptom in asubject, comprising administering an effective amount of a PI3K-γinhibitor to a subject in need thereof, wherein one or more of theadverse effects associated with administration of inhibitors for one ormore other isoforms of PI3K are reduced. In one embodiment, the one ormore other isoforms of PI3K is PI3K-α, PI3K-β, and/or PI3K-δ. In oneembodiment, the one or more other isoforms of PI3K is PI3K-α and/orPI3K-β. In one embodiment, the method is for treating rheumatoidarthritis in a subject, or for reducing a rheumatoidarthritis-associated symptom in a subject. In another embodiment, themethod is for treating asthma in a subject, or for reducing anasthma-associated symptom in a subject.

In some embodiments, provided herein are methods of using a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, to treat diseaseconditions, including, but not limited to, diseases associated withmalfunctioning of one or more types of PI3 kinase In one embodiment, adetailed description of conditions and disorders mediated by p110δkinase activity is set forth in Sadu et al., WO 01/81346, which isincorporated herein by reference in its entirety for all purposes.

In some embodiments, the disclosure relates to a method of treating ahyperproliferative disorder in a subject that comprises administering tosaid subject a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or a pharmaceuticalcomposition as provided herein. In some embodiments, said method relatesto the treatment of cancer such as acute myeloid leukemia, thymus,brain, lung, squamous cell, skin, eye, retinoblastoma, intraocularmelanoma, oral cavity and oropharyngeal, bladder, gastric, stomach,pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver,ovarian, prostate, colorectal, esophageal, testicular, gynecological,thyroid, CNS, PNS, AIDS-related (e.g., Lymphoma and Kaposi's Sarcoma) orviral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)).

In some embodiments, the disclosure relates to a method of treating asolid tumor. In some embodiments, the solid tumor is selected fromovarian cancer, colon cancer, fibrosarcoma, pancreatic cancer, lungcancer, breast cancer, lymphoma, melanoma, and glioblastoma.

As used herein “solid tumor” refers to an abnormal mass of tissue. Solidtumors may be benign or malignant. A solid tumor grows in an anatomicalsite outside the bloodstream and requires the formation of small bloodvessels and capillaries to supply nutrients, etc. to the growing tumormass. Solid tumors are named for the type of cells that form them.Non-limiting examples of solid tumors are sarcomas, carcinomas(epithelial tumors), melanomas, and glioblastomas.

In some embodiments, the disclosure relates to a method of inhibitinggrowth of a tumor. “Inhibiting growth of a tumor” refers to slowingtumor growth and/or reducing tumor size. “Inhibiting growth of a tumor”thus includes killing tumor cells as well as slowing or arresting tumorcell growth.

In some embodiments, the disclosure relates to a method of treating asolid tumor comprising administering to a subject a gamma selectivecompound.

In some embodiments, the disclosure relates to a method of treating aninflammatory disease comprising administering to a subject a gammaselective compound.

In some embodiment, the gamma selective compound has a delta/gammaselectivity ratio of >1 to <10, 10 to <50, or 50 to <350 can be combinedwith a compound that has a gamma/delta selectivity ratio of greater thana factor of about 1, greater than a factor of about 2, greater than afactor of about 3, greater than a factor of about 5, greater than afactor of about 10, greater than a factor of about 50, greater than afactor of about 100, greater than a factor of about 200, greater than afactor of about 400, greater than a factor of about 600, greater than afactor of about 800, greater than a factor of about 1000, greater than afactor of about 1500, greater than a factor of about 2000, greater thana factor of about 5000, greater than a factor of about 10,000, orgreater than a factor of about 20,000.

Patients that can be treated with a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, according to the methods as provided herein include, forexample, but not limited to, patients that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma, lobular carcinoma, medullary carcinomas, colloidcarcinomas, tubular carcinomas, and inflammatory breast cancer; ovariancancer, including epithelial ovarian tumors such as adenocarcinoma inthe ovary and an adenocarcinoma that has migrated from the ovary intothe abdominal cavity; uterine cancer; cervical cancer such asadenocarcinoma in the cervix epithelial including squamous cellcarcinoma and adenocarcinomas; prostate cancer, such as a prostatecancer selected from the following: an adenocarcinoma or anadenocarcinoma that has migrated to the bone; pancreatic cancer such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, NK cellleukemia (e.g., blastic plasmacytoid dendritic cell neoplasm), acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer; kidney cancer; thyroid cancer such as papillary, follicular,medullary and anaplastic; lymphoma such as diffuse large B-celllymphoma, B-cell immunoblastic lymphoma, NK cell lymphoma (e.g., blasticplasmacytoid dendritic cell neoplasm), and Burkitt lymphoma; Kaposi'sSarcoma; viral-induced cancers including hepatitis B virus (HBV),hepatitis C virus (HCV), and hepatocellular carcinoma; humanlymphotropic virus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma;and human papilloma virus (HPV) and cervical cancer; central nervoussystem cancers (CNS) such as primary brain tumor, which includes gliomas(astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme),oligodendroglioma, ependymoma, meningioma, lymphoma, schwannoma, andmedulloblastoma; peripheral nervous system (PNS) cancers such asacoustic neuromas and malignant peripheral nerve sheath tumor (MPNST)including neurofibromas and schwannomas, malignant fibrocytoma,malignant fibrous histiocytoma, malignant meningioma, malignantmesothelioma, and malignant mixed Müllerian tumor; oral cavity andoropharyngeal cancers such as, hypopharyngeal cancer, laryngeal cancer,nasopharyngeal cancer, and oropharyngeal cancer; stomach cancers such aslymphomas, gastric stromal tumors, and carcinoid tumors; testicularcancers such as germ cell tumors (GCTs), which include seminomas andnonseminomas, and gonadal stromal tumors, which include Leydig celltumors and Sertoli cell tumors; thymus cancer such as to thymomas,thymic carcinomas, Hodgkin lymphoma, non-Hodgkin lymphomas carcinoids orcarcinoid tumors; rectal cancer; and colon cancer.

Patients that can be treated with compounds provided herein, orpharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods provided hereininclude, for example, patients that have been diagnosed as havingconditions including, but not limited to, acoustic neuroma,adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g.,lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), benignmonoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma),bladder cancer, breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast), brain cancer (e.g., meningioma; glioma, e.g.,astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer,cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma,chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma), epithelial carcinoma,ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multipleidiopathic hemorrhagic sarcoma), endometrial cancer, esophageal cancer(e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewingsarcoma, familiar hypereosinophilia, gastric cancer (e.g., stomachadenocarcinoma), gastrointestinal stromal tumor (GIST), head and neckcancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g.,oral squamous cell carcinoma (OSCC)), heavy chain disease (e.g., alphachain disease, gamma chain disease, mu chain disease), hemangioblastoma,inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidneycancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma),liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma),lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer(SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung),leukemia (e.g., acute lymphocytic leukemia (ALL), which includesB-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL),prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) andWaldenstrom's macroglobulinemia (WM); peripheral T cell lymphomas(PTCL), adult T cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma(CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease andReed-Stemberg disease; acute myelocytic leukemia (AML), chronicmyelocytic leukemia (CML), chronic lymphocytic leukemia (CLL)), lymphoma(e.g., Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), follicularlymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma(MCL)), leiomyosarcoma (LMS), mastocytosis (e.g., systemicmastocytosis), multiple myeloma (MM), myelodysplastic syndrome (MDS),mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis),neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrinetumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g.,cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma), Paget's disease of the vulva, Paget's disease of thepenis, papillary adenocarcinoma, pancreatic cancer (e.g., pancreaticandenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)),pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g.,prostate adenocarcinoma), rhabdomyosarcoma, retinoblastoma, salivarygland cancer, skin cancer (e.g., squamous cell carcinoma (SCC),keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowelcancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignantfibrous histiocytoma (MFH), liposarcoma, malignant peripheral nervesheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma),sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicularcancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer(e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma(PTC), medullary thyroid cancer), and Waldenstrom's macroglobulinemia.

Without being limited by a particular theory, in one embodiment, thecancer or disease being treated or prevented, such as a blood disorderor hematologic malignancy, has a high expression level of one or morePI3K isoform(s) (e.g., PI3K-α, PI3K-β, PI3K-δ, or PI3K-γ, or acombination thereof). In one embodiment, the cancer or disease that canbe treated or prevented by methods, compositions, or kits providedherein includes a blood disorder or a hematologic malignancy, including,but not limited to, myeloid disorder, lymphoid disorder, leukemia,lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease(MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), amongothers. In one embodiment, the blood disorder or the hematologicmalignancy includes, but is not limited to, acute lymphoblastic leukemia(ALL), T-cell ALL (T-ALL), B-cell ALL (B-ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia(CML), blast phase CML, small lymphocytic lymphoma (SLL), CLL/SLL, blastphase CLL, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), B-cellNHL, T-cell NHL, indolent NHL (iNHL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), aggressive B-cell NHL, B-celllymphoma (BCL), Richter's syndrome (RS), T-cell lymphoma (TCL),peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL),transformed mycosis fungoides, Sézary syndrome, anaplastic large-celllymphoma (ALCL), follicular lymphoma (FL), Waldenström macroglobulinemia(WM), lymphoplasmacytic lymphoma, Burkitt lymphoma, multiple myeloma(MM), amyloidosis, MPD, essential thrombocytosis (ET), myelofibrosis(MF), polycythemia vera (PV), chronic myelomonocytic leukemia (CMML),myelodysplastic syndrome (MDS), angioimmunoblastic lymphoma, high-riskMDS, and low-risk MDS. In one embodiment, the hematologic malignancy isrelapsed. In one embodiment, the hematologic malignancy is refractory.In one embodiment, the cancer or disease is in a pediatric patient(including an infantile patient). In one embodiment, the cancer ordisease is in an adult patient. Additional embodiments of a cancer ordisease being treated or prevented by methods, compositions, or kitsprovided herein are described herein elsewhere.

In exemplary embodiments, the cancer or hematologic malignancy is CLL.In exemplary embodiments, the cancer or hematologic malignancy isCLL/SLL. In exemplary embodiments, the cancer or hematologic malignancyis blast phase CLL. In exemplary embodiments, the cancer or hematologicmalignancy is SLL.

In exemplary embodiments, the cancer or hematologic malignancy is iNHL.In exemplary embodiments, the cancer or hematologic malignancy is DLBCL.In exemplary embodiments, the cancer or hematologic malignancy is B-cellNHL (e.g., aggressive B-cell NHL). In exemplary embodiments, the canceror hematologic malignancy is MCL. In exemplary embodiments, the canceror hematologic malignancy is RS. In exemplary embodiments, the cancer orhematologic malignancy is AML. In exemplary embodiments, the cancer orhematologic malignancy is MM. In exemplary embodiments, the cancer orhematologic malignancy is ALL. In exemplary embodiments, the cancer orhematologic malignancy is T-ALL. In exemplary embodiments, the cancer orhematologic malignancy is B-ALL. In exemplary embodiments, the cancer orhematologic malignancy is TCL. In exemplary embodiments, the cancer orhematologic malignancy is ALCL. In exemplary embodiments, the cancer orhematologic malignancy is leukemia. In exemplary embodiments, the canceror hematologic malignancy is lymphoma. In exemplary embodiments, thecancer or hematologic malignancy is T-cell lymphoma. In exemplaryembodiments, the cancer or hematologic malignancy is MDS (e.g., lowgrade MDS). In exemplary embodiments, the cancer or hematologicmalignancy is MPD. In exemplary embodiments, the cancer or hematologicmalignancy is a mast cell disorder. In exemplary embodiments, the canceror hematologic malignancy is Hodgkin lymphoma (HL). In exemplaryembodiments, the cancer or hematologic malignancy is non-Hodgkinlymphoma. In exemplary embodiments, the cancer or hematologic malignancyis PTCL. In exemplary embodiments, the cancer or hematologic malignancyis CTCL (e.g., mycosis fungoides or Sézary syndrome). In exemplaryembodiments, the cancer or hematologic malignancy is WM. In exemplaryembodiments, the cancer or hematologic malignancy is CML. In exemplaryembodiments, the cancer or hematologic malignancy is FL. In exemplaryembodiments, the cancer or hematologic malignancy is transformed mycosisfungoides. In exemplary embodiments, the cancer or hematologicmalignancy is Sézary syndrome. In exemplary embodiments, the cancer orhematologic malignancy is acute T-cell leukemia. In exemplaryembodiments, the cancer or hematologic malignancy is acute B-cellleukemia. In exemplary embodiments, the cancer or hematologic malignancyis Burkitt lymphoma. In exemplary embodiments, the cancer or hematologicmalignancy is myeloproliferative neoplasms. In exemplary embodiments,the cancer or hematologic malignancy is splenic marginal zone. Inexemplary embodiments, the cancer or hematologic malignancy is nodalmarginal zone. In exemplary embodiments, the cancer or hematologicmalignancy is extranodal marginal zone.

In one embodiment, the cancer or hematologic malignancy is a B celllymphoma. In a specific embodiment, provided herein is a method oftreating or managing a B cell lymphoma comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof. Also provided herein is a method of treating orlessening one or more of the symptoms associated with a B cell lymphomacomprising administering to a patient a therapeutically effective amountof a compound provided herein, or a pharmaceutically acceptablederivative (e.g., salt or solvate) thereof. In one embodiment, the Bcell lymphoma is iNHL. In another embodiment, the B cell lymphoma isfollicular lymphoma. In another embodiment, the B cell lymphoma isWaldenstrom macroglobulinemia (lymphoplasmacytic lymphoma). In anotherembodiment, the B cell lymphoma is marginal zone lymphoma (MZL). Inanother embodiment, the B cell lymphoma is MCL. In another embodiment,the B cell lymphoma is HL. In another embodiment, the B cell lymphoma isaNHL. In another embodiment, the B cell lymphoma is DLBCL. In anotherembodiment, the B cell lymphoma is Richters lymphoma.

In one embodiment, the cancer or hematologic malignancy is a T celllymphoma. In a specific embodiment, provided herein is a method oftreating or managing a T cell lymphoma comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof. Also provided herein is a method of treating orlessening one or more of the symptoms associated with a T cell lymphomacomprising administering to a patient a therapeutically effective amountof a compound provided herein, or a pharmaceutically acceptablederivative (e.g., salt or solvate) thereof. In one embodiment, the Tcell lymphoma is peripheral T cell lymphoma (PTCL). In anotherembodiment, the T cell lymphoma is cutaneous T cell lymphoma (CTCL).

In one embodiment, the cancer or hematologic malignancy is Sézarysyndrome. In a specific embodiment, provided herein is a method oftreating or managing Sézary syndrome comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof. Also provided herein is a method of treating orlessening one or more of the symptoms associated with Sézary syndromecomprising administering to a patient a therapeutically effective amountof a compound provided herein, or a pharmaceutically acceptablederivative (e.g., salt or solvate) thereof. The symptoms associated withSézary syndrome include, but are not limited to, epidermotropism byneoplastic CD4+ lymphocytes, Pautrier's microabscesses, erythroderma,lymphadenopathy, atypical T cells in the peripheral blood, andhepatosplenomegaly In one embodiment, the therapeutically effectiveamount for treating or managing Sézary syndrome is from about 25 mg to75 mg, administered twice daily. In other embodiments, thetherapeutically effective amount is from about 50 mg to about 75 mg,from about 30 mg to about 65 mg, from about 45 mg to about 60 mg, fromabout 30 mg to about 50 mg, or from about 55 mg to about 65 mg, each ofwhich is administered twice daily. In one embodiment, the effectiveamount is about 60 mg, administered twice daily.

In one embodiment, the cancer or hematologic malignancy is relapsed. Inone embodiment, the cancer or hematologic malignancy is refractory. Incertain embodiments, the cancer being treated or prevented is a specificsub-type of cancer described herein. In certain embodiments, thehematologic malignancy being treated or prevented is a specific sub-typeof hematologic malignancy described herein. Certain classifications oftype or sub-type of a cancer or hematologic malignancy provided hereinis known in the art. Without being limited by a particular theory, it isbelieved that many of the cancers that become relapsed or refractorydevelop resistance to the particular prior therapy administered to treatthe cancers. Thus, without being limited by a particular theory, acompound provided herein can provide a second line therapy by providingan alternative mechanism to treat cancers different from thosemechanisms utilized by certain prior therapies. Accordingly, in oneembodiment, provided herein is a method of treating or managing canceror hematologic malignancy comprising administering to a patient atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable derivative (e.g., salt or solvate) thereof,wherein the cancer or hematologic malignancy is relapsed after, orrefractory to, a prior therapy.

In exemplary embodiments, the cancer or hematologic malignancy isrefractory iNHL. In exemplary embodiments, the cancer or hematologicmalignancy is refractory CLL. In exemplary embodiments, the cancer orhematologic malignancy is refractory SLL. In exemplary embodiments, thecancer or hematologic malignancy is refractory to rituximab therapy. Inexemplary embodiments, the cancer or hematologic malignancy isrefractory to chemotherapy. In exemplary embodiments, the cancer orhematologic malignancy is refractory to radioimmunotherapy (RIT). Inexemplary embodiments, the cancer or hematologic malignancy is iNHL, FL,splenic marginal zone, nodal marginal zone, extranodal marginal zone, orSLL, the cancer or hematologic malignancy is refractory to rituximabtherapy, chemotherapy, and/or RIT.

In another exemplary embodiment, the cancer or hematologic malignancy islymphoma, and the cancer is relapsed after, or refractory to, thetreatment by a BTK inhibitor such as, but not limited to, ibrutinib. Inanother exemplary embodiment, the cancer or hematologic malignancy isCLL, and the cancer is relapsed after, or refractory to, the treatmentby a BTK inhibitor such as, but not limited to, ibrutinib and AVL-292.

In one embodiment, provided herein is a method of treating aninflammation disorder, including autoimmune diseases in a subject. Themethod comprises administering to said subject a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein. Examples ofautoimmune diseases include but are not limited to acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), aplastic anemia, autoimmune hepatitis, autoimmune skindisease, coeliac disease, Crohn's disease, Diabetes mellitus (type 1),Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS),Hashimoto's disease, lupus erythematosus, multiple sclerosis, myastheniagravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord'sthyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis,psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis (also known as “giant cell arteritis”),warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis (e.g., inflammatory alopecia), Chagas disease, chronicfatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, and vulvodynia. Other disorders includebone-resorption disorders and thrombosis.

Inflammation takes on many forms and includes, but is not limited to,acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse,disseminated, exudative, fibrinous, fibrosing, focal, granulomatous,hyperplastic, hypertrophic, interstitial, metastatic, necrotic,obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple,specific, subacute, suppurative, toxic, traumatic, and/or ulcerativeinflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoidarthritis and Reiter's arthritis), ankylosing spondylitis, amylosis,amyotrophic lateral sclerosis, autoimmune diseases, allergies orallergic reactions, atherosclerosis, bronchitis, bursitis, chronicprostatitis, conjunctivitis, Chagas disease, chronic obstructivepulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., typeI diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g.,psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, polymyalgiarheumatic, reperfusion injury, regional enteritis, rheumatic fever,systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia.

Immune disorders, such as auto-immune disorders, include, but are notlimited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), relapsing polychondritis (e.g.,atrophic polychondritis and systemic polychondromalacia), and disordersameliorated by a gastroprokinetic agent (e.g., ileus, postoperativeileus and ileus during sepsis; gastroesophageal reflux disease (GORD, orits synonym GERD); eosinophilic esophagitis, gastroparesis such asdiabetic gastroparesis; food intolerances and food allergies and otherfunctional bowel disorders, such as non-ulcerative dyspepsia (NUD) andnon-cardiac chest pain (NCCP, including costo-chondritis)). In certainembodiments, a method of treating inflammatory or autoimmune diseases isprovided comprising administering to a subject (e.g., a mammal) atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, that selectively inhibit PI3K-δ and/or PI3K-γ as compared to allother type I PI3 kinases Such selective inhibition of PI3K-δ and/orPI3K-γ can be advantageous for treating any of the diseases orconditions described herein. For example, selective inhibition of PI3K-δand/or PI3K-γ can inhibit inflammatory responses associated withinflammatory diseases, autoimmune disease, or diseases related to anundesirable immune response including, but not limited to asthma,emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupuserythematosus, anaphylaxsis, or graft versus host disease. Selectiveinhibition of PI3K-δ and/or PI3K-γ can further provide for a reductionin the inflammatory or undesirable immune response without a concomitantreduction in the ability to reduce a bacterial, viral, and/or fungalinfection. Selective inhibition of both PI3K-δ and PI3K-γ can beadvantageous for inhibiting the inflammatory response in the subject toa greater degree than that would be provided for by inhibitors thatselectively inhibit PI3K -δ or PI3K-γ alone. In one aspect, one or moreof the subject methods are effective in reducing antigen specificantibody production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold,7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold,750-fold, or about 1000-fold or more. In another aspect, one or more ofthe subject methods are effective in reducing antigen specific IgG3and/or IgGM production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold,7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold,750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rheumatoid arthritis including,but not limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, or60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, or 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, or 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, or 90%, or more. In still another aspect, the subjectmethods are effective in reducing knee histopathology scores by about5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, or 90%, or more.

In some embodiments, provided herein are methods for treating disordersor conditions in which the 6 isoform of PI3K is implicated to a greaterextent than other PI3K isoforms such as PI3K-α and/or PI3K-β. In someembodiments, provided herein are methods for treating disorders orconditions in which the γ isoform of PI3K is implicated to a greaterextent than other PI3K isoforms such as PI3K-α and/or PI3K-β. Selectiveinhibition of PI3K-δ and/or PI3K-γ can provide advantages over usingless selective compounds which inhibit PI3K-α and/or PI3K-β, such as animproved side effects profile or lessened reduction in the ability toreduce a bacterial, viral, and/or fungal infection.

In other embodiments, provided herein are methods of using a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, to treat respiratorydiseases including, but not limited to, diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term include, but arenot limited to: chronic bronchitis, emphysema, and bronchiectasis.

In another embodiment, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein is used forthe treatment of asthma. Also, a compound provided herein, or apharmaceutically acceptable form thereof, or a pharmaceuticalcomposition described herein, can be used for the treatment ofendotoxemia and sepsis. In one embodiment, the compounds orpharmaceutical compositions described herein are used to for thetreatment of rheumatoid arthritis (RA). In yet another embodiment, thecompounds or pharmaceutical compositions described herein is used forthe treatment of contact or atopic dermatitis. Contact dermatitisincludes irritant dermatitis, phototoxic dermatitis, allergicdermatitis, photoallergic dermatitis, contact urticaria, systemiccontact-type dermatitis and the like. Irritant dermatitis can occur whentoo much of a substance is used on the skin of when the skin issensitive to certain substance. Atopic dermatitis, sometimes calledeczema, is a kind of dermatitis, an atopic skin disease.

In some embodiments, the disclosure provides a method of treatingdiseases related to vasculogenesis or angiogenesis in a subject thatcomprises administering to said subject a therapeutically effectiveamount of a compound provided herein, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein. In some embodiments, saidmethod is for treating a disease selected from tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis and chronicinflammatory demyelinating polyneuropathy, atherosclerosis, inflammatorybowel disease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In addition, the compounds described herein can be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

In some embodiments, provided herein is a method of treating acardiovascular disease in a subject that comprises administering to saidsubject a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or a pharmaceuticalcomposition as provided herein. Examples of cardiovascular conditionsinclude, but are not limited to, atherosclerosis, restenosis, vascularocclusion and carotid obstructive disease.

In some embodiments, the disclosure relates to a method of treatingdiabetes in a subject that comprises administering to said subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein.

In addition, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can be usedto treat acne. In certain embodiments, the inflammatory condition and/orimmune disorder is a skin condition. In some embodiments, the skincondition is pruritus (itch), psoriasis, eczema, burns or dermatitis. Incertain embodiments, the skin condition is psoriasis. In certainembodiments, the skin condition is pruritis.

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

Further, a compound provided herein, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, can be used for thetreatment of glomerulonephritis. Glomerulonephritis is a primary orsecondary autoimmune renal disease characterized by inflammation of theglomeruli. It can be asymptomatic, or present with hematuria and/orproteinuria. There are many recognized types, divided in acute, subacuteor chronic glomerulonephritis. Causes are infectious (bacterial, viralor parasitic pathogens), autoimmune or paraneoplastic.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for thetreatment of multiorgan failure. Also provided herein are compounds, orpharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of liver diseases (including diabetes), gall bladderdisease (including gallstones), pancreatitis or kidney disease(including proliferative glomerulonephritis and diabetes-induced renaldisease) or pain in a subject.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for theprevention of blastocyte implantation in a subject.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for thetreatment of disorders involving platelet aggregation or plateletadhesion, including, but not limited to, Idiopathic thrombocytopenicpurpura, Bernard-Soulier syndrome, Glanzmann's thrombasthenia, Scott'ssyndrome, von Willebrand disease, Hermansky-Pudlak Syndrome, and Grayplatelet syndrome.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for thetreatment of a disease which is skeletal muscle atrophy, skeletal ormuscle hypertrophy. In some embodiments, provided herein are compounds,or pharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of disorders that include, but are not limited to,cancers as discussed herein, transplantation-related disorders (e.g.,lowering rejection rates, graft-versus-host disease, etc.), muscularsclerosis (MS), allergic disorders (e.g., arthritis, allergicencephalomyelitis) and other immunosuppressive-related disorders,metabolic disorders (e.g., diabetes), reducing intimal thickeningfollowing vascular injury, and misfolded protein disorders (e.g.,Alzheimer's Disease, Gaucher's Disease, Parkinson's Disease,Huntington's Disease, cystic fibrosis, macular degeneration, retinitispigmentosa, and prion disorders) (as mTOR inhibition can alleviate theeffects of misfolded protein aggregates). The disorders also includehamartoma syndromes, such as tuberous sclerosis and Cowden Disease (alsotermed Cowden syndrome and multiple hamartoma syndrome).

Additionally, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can be usedfor the treatment of bursitis, lupus, acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), amyloidosis (including systemic and localizedamyloidosis; and primary and secondary amyloidosis), aplastic anemia,autoimmune hepatitis, coeliac disease, crohn's disease, diabetesmellitus (type 1), eosinophilic gastroenterides, goodpasture's syndrome,graves' disease, guillain-barré syndrome (GBS), hashimoto's disease,inflammatory bowel disease, lupus erythematosus (including cutaneouslupus erythematosus and systemic lupus erythematosus), myastheniagravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, ord'sthyroiditis, ostheoarthritis, uveoretinitis, pemphigus, polyarthritis,primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, wegener'sgranulomatosis, alopecia universalis, chagas' disease, chronic fatiguesyndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, vulvodynia, appendicitis, arteritis,arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis,cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis,cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis,hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis,myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, uveitis (e.g., ocularuveitis), vaginitis, vasculitis, or vulvitis.

Further, the compounds provided herein may be used for the treatment ofPerennial allergic rhinitis, Mesenteritis, Peritonitis, Acrodermatitis,Angiodermatitis, Atopic dermatitis, Contact dermatitis, Eczema, Erythemamultiforme, Intertrigo, Stevens Johnson syndrome, Toxic epidermalnecrolysis, Skin allergy, Severe allergic reaction/anaphylaxis, Allergicgranulomatosis, Wegener granulomatosis, Allergic conjunctivitis,Chorioretinitis, Conjunctivitis, Infectious keratoconjunctivitis,Keratoconjunctivitis, Ophthalmia neonatorum, Trachoma, Uveitis, Ocularinflammation, Blepharoconjunctivitis, Mastitis, Gingivitis,Pericoronitis, Pharyngitis, Rhinopharyngitis, Sialadenitis,Musculoskeletal system inflammation, Adult onset Stills disease, Behcetsdisease, Bursitis, Chondrocalcinosis, Dactylitis, Felty syndrome, Gout,Infectious arthritis, Lyme disease, Inflammatory osteoarthritis,Periarthritis, Reiter syndrome, Ross River virus infection, AcuteRespiratory, Distress Syndrome, Acute bronchitis, Acute sinusitis,Allergic rhinitis, Asthma, Severe refractory asthma, Pharyngitis,Pleurisy, Rhinopharyngitis, Seasonal allergic rhinitis, Sinusitis,Status asthmaticus, Tracheobronchitis, Rhinitis, Serositis, Meningitis,Neuromyelitis optica, Poliovirus infection, Alport syndrome, Balanitis,Epididymitis, Epididymo orchitis, Focal segmental, Glomerulosclerosis,Glomerulonephritis, IgA Nephropathy (Berger's Disease), Orchitis,Parametritis, Pelvic inflammatory disease, Prostatitis, Pyelitis,Pyelocystitis, Pyelonephritis, Wegener granulomatosis, Hyperuricemia,Aortitis, Arteritis, Chylopericarditis, Dressler syndrome, Endarteritis,Endocarditis, Extracranial temporal arteritis, HIV associated arteritis,Intracranial temporal arteritis, Kawasaki disease, Lymphangiophlebitis,Mondor disease, Periarteritis, or Pericarditis.

In other aspects, the compounds provided herein are used for thetreatment of Autoimmune hepatitis, Jejunitis, Mesenteritis, Mucositis,Non alcoholic steatohepatitis, Non viral hepatitis, Autoimmunepancreatitis, Perihepatitis, Peritonitis, Pouchitis, Proctitis,Pseudomembranous colitis, Rectosigmoiditis, Salpingoperitonitis,Sigmoiditis, Steatohepatitis, Ulcerative colitis, Churg Strausssyndrome, Ulcerative proctitis, Irritable bowel syndrome,Gastrointestinal inflammation, Acute enterocolitis, Anusitis, Balsernecrosis, Cholecystitis, Colitis, Crohns disease, Diverticulitis,Enteritis, Enterocolitis, Enterohepatitis, Eosinophilic esophagitis,Esophagitis, Gastritis, Hemorrhagic enteritis, Hepatitis, Hepatitisvirus infection, Hepatocholangitis, Hypertrophic gastritis, Ileitis,Ileocecitis, Sarcoidosis, Inflammatory bowel disease, Ankylosingspondylitis, Rheumatoid arthritis, Juvenile rheumatoid arthritis,Psoriasis, Psoriatic arthritis, Lupus (cutaneous/systemic/nephritis),AIDS, Agammaglobulinemia, AIDS related complex, Brutons disease ,Chediak Higashi syndrome, Common variable immunodeficiency, DiGeorgesyndrome, Dysgammaglobulinemia, Immunoglobulindeficiency, Job syndrome,Nezelof syndrome, Phagocyte bactericidal disorder, Wiskott Aldrichsyndrome, Asplenia, Elephantiasis, Hypersplenism, Kawasaki disease,Lymphadenopathy, Lymphedema, Lymphocele, Nonne Milroy Meige syndrome,Spleen disease, Splenomegaly, Thymoma, Thymus disease, Perivasculitis,Phlebitis, Pleuropericarditis, Polyarteritis nodosa, Vasculitis,Takayasus arteritis, Temporal arteritis, Thromboangiitis,Thromboangiitis obliterans, Thromboendocarditis, Thrombophlebitis, orCOPD.

In another aspect, provided herein are methods of disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Themethod includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound provided herein.

In another aspect, provided herein are methods for the treatment of anophthalmic disease by administering one or more of compounds providedherein, or pharmaceutically acceptable forms thereof, or pharmaceuticalcompositions as provided herein, to the eye of a subject.

Methods are further provided for administering the compounds providedherein via eye drop, intraocular injection, intravitreal injection,topically, or through the use of a drug eluting device, microcapsule,implant, or microfluidic device. In some cases, the compounds providedherein are administered with a carrier or excipient that increases theintraocular penetrance of the compound such as an oil and water emulsionwith colloid particles having an oily core surrounded by an interfacialfilm.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: Crohn's disease; cutaneous lupus;multiple sclerosis; rheumatoid arthritis; and systemic lupuserythematosus.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: ankylosing spondylitis; chronicobstructive pulmonary disease; myasthenia gravis; ocular uveitis,psoriasis; and psoriatic arthritis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: adult-onset Still's disease;inflammatory alopecia; amyloidosis; antiphospholipid syndrome;autoimmune hepatitis; autoimmune skin disease, Behcet's disease; chronicinflammatory demyelinating polyneuropathy; eosinophilic gastroenteritis;inflammatory myopathies, pemphigus, polymyalgia rheumatica; relapsingpolychondritis; Sjorgen's syndrome; temporal arthritis; ulcerativecolitis; vasculis; vitiligo, and Wegner's granulomatosis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: gout flare; sacoidosis; and systemicsclerosis.

In certain embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: asthma; arthritis (e.g., rheumatoidarthritis and psoriatic arthritis); psoriasis; scleroderma; myositis(e.g., dermatomyositis); lupus (e.g., cutaneous lupus erythematosus(“CLE”) or systemic lupus erythematosus (“SLE”)); or Sjögren's syndrome.

Efficacy of a compound provided herein in treating, preventing and/ormanaging the disease or disorder can be tested using various animalmodels known in the art. For example: efficacy in treating, preventingand/or managing asthma can be assessed using ova induced asthma modeldescribed, for example, in Lee et al. (2006) J Allergy Clin Immunol118(2):403-9; efficacy in treating, preventing and/or managing arthritis(e.g., rheumatoid or psoriatic arthritis) can be assessed usingautoimmune animal models described, for example, in Williams et al.(2010) Chem Biol, 17(2):123-34, WO 2009/088986, WO2009/088880, and WO2011/008302; efficacy in treating, preventing and/or managing psoriasiscan be assessed using transgenic or knockout mouse model with targetedmutations in epidermis, vasculature or immune cells, mouse modelresulting from spontaneous mutations, and immuno-deficient mouse modelwith xenotransplantation of human skin or immune cells, all of which aredescribed, for example, in Boehncke et al. (2007) Clinics inDermatology, 25: 596-605; efficacy in treating, preventing and/ormanaging fibrosis or fibrotic condition can be assessed using theunilateral ureteral obstruction model of renal fibrosis (see Chevalieret al., Kidney International (2009) 75:1145-1152), the bleomycin inducedmodel of pulmonary fibrosis (see Moore and Hogaboam, Am. J. Physiol.Lung. Cell. Mol. Physiol. (2008) 294:L152-L160), a variety ofliver/biliary fibrosis models (see Chuang et al., Clin Liver Dis (2008)12:333-347 and Omenetti, A. et al. (2007) Laboratory Investigation87:499-514 (biliary duct-ligated model)), or a number of myelofibrosismouse models (see Varicchio, L. et al. (2009) Expert Rev. Hematol.2(3):315-334); efficacy in treating, preventing and/or managingscleroderma can be assessed using mouse model induced by repeated localinjections of bleomycin (“BLM”) described, for example, in Yamamoto etal. (1999) J Invest Dermatol 112: 456-462; efficacy in treating,preventing and/or managing dermatomyositis can be assessed usingmyositis mouse model induced by immunization with rabbit myosindescribed, for example, in Phyanagi et al. (2009) Arthritis &Rheumatism, 60(10): 3118-3127; efficacy in treating, preventing and/ormanaging lupus (e.g., CLE or SLE) can be assessed using various animalmodels described, for example, in Ghoreishi et al. (2009) Lupus, 19:1029-1035, Ohl et al. (2011) Journal of Biomedicine and Biotechnology,Article ID 432595 (14 pages), Xia et al. (2011) Rheumatology,50:2187-2196, Pau et al. (2012) PLoS ONE, 7(5):e36761 (15 pages),Mustafa et al. (2011) Toxicology, 290:156-168, Ichikawa et al. (2012)Arthritis and Rheumatism, 62(2): 493-503, Ouyang et al. (2012) J MolMed, DOI 10.1007/s00109-012-0866-3 (10 pages), Rankin et al. (2012)Journal of Immunology, 188:1656-1667; and efficacy in treating,preventing and/or managing Sjögren's syndrome can be assessed usingvarious mouse models described, for example, in Chiorini et al. (2009)Journal of Autoimmunity, 33: 190-196.

In one embodiment, provided herein is a method of treating, preventingand/or managing asthma. As used herein, “asthma” encompasses airwayconstriction regardless of the cause. Common triggers of asthma include,but are not limited to, exposure to an environmental stimulants (e.g.,allergens), cold air, warm air, perfume, moist air, exercise orexertion, and emotional stress. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith asthma Examples of the symptoms include, but are not limited to,severe coughing, airway constriction and mucus production.

In one embodiment, provided herein is a method of treating, preventingand/or managing arthritis. As used herein, “arthritis” encompasses alltypes and manifestations of arthritis. Examples include, but are notlimited to, crystalline arthritis, osteoarthritis, psoriatic arthritis,gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter'sarthritis. In one embodiment, the disease or disorder is rheumatoidarthritis. In another embodiment, the disease or disorder is psoriaticarthritis. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with arthritis. Examplesof the symptoms include, but are not limited to, joint pain, whichprogresses into joint deformation, or damages in body organs such as inblood vessels, heart, lungs, skin, and muscles.

In one embodiment, provided herein is a method of treating, preventingand/or managing psoriasis. As used herein, “psoriasis” encompasses alltypes and manifestations of psoriasis. Examples include, but are notlimited to, plaque psoriasis (e.g., chronic plaque psoriasis, moderateplaque psoriasis and severe plaque psoriasis), guttate psoriasis,inverse psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermicpsoriasis, psoriasis associated with inflammatory bowel disease (IBD),and psoriasis associated with rheumatoid arthritis (RA). Also providedherein is a method of treating, preventing and/or managing one or moresymptoms associated with psoriasis. Examples of the symptoms include,but are not limited to: red patches of skin covered with silvery scales;small scaling spots; dry, cracked skin that may bleed; itching; burning;soreness; thickened, pitted or ridged nails; and swollen and stiffjoints.

In one embodiment, provided herein is a method of treating, preventingand/or managing fibrosis and fibrotic condition. As used herein,“fibrosis” or “fibrotic condition encompasses all types andmanifestations of fibrosis or fibrotic condition. Examples include, butare not limited to, formation or deposition of tissue fibrosis; reducingthe size, cellularity (e.g., fibroblast or immune cell numbers),composition; or cellular content, of a fibrotic lesion; reducing thecollagen or hydroxyproline content, of a fibrotic lesion; reducingexpression or activity of a fibrogenic protein; reducing fibrosisassociated with an inflammatory response; decreasing weight lossassociated with fibrosis; or increasing survival.

In certain embodiments, the fibrotic condition is primary fibrosis. Inone embodiment, the fibrotic condition is idiopathic. In otherembodiments, the fibrotic condition is associated with (e.g., issecondary to) a disease (e.g., an infectious disease, an inflammatorydisease, an autoimmune disease, a malignant or cancerous disease, and/ora connective disease); a toxin; an insult (e.g., an environmental hazard(e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarettesmoking, a wound); a medical treatment (e.g., surgical incision,chemotherapy or radiation), or a combination thereof.

In some embodiments, the fibrotic condition is associated with anautoimmune disease selected from scleroderma or lupus, e.g., systemiclupus erythematosus. In some embodiments, the fibrotic condition issystemic. In some embodiments, the fibrotic condition is systemicsclerosis (e.g., limited systemic sclerosis, diffuse systemic sclerosis,or systemic sclerosis sine scleroderma), nephrogenic systemic fibrosis,cystic fibrosis, chronic graft vs. host disease, or atherosclerosis.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung, a fibrotic condition of the liver, a fibrotic condition ofthe heart or vasculature, a fibrotic condition of the kidney, a fibroticcondition of the skin, a fibrotic condition of the gastrointestinaltract, a fibrotic condition of the bone marrow or a hematopoietictissue, a fibrotic condition of the nervous system, a fibrotic conditionof the eye, or a combination thereof.

In other embodiment, the fibrotic condition affects a tissue chosen fromone or more of muscle, tendon, cartilage, skin (e.g., skin epidermis orendodermis), cardiac tissue, vascular tissue (e.g., artery, vein),pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterinetissue, ovarian tissue, neural tissue, testicular tissue, peritonealtissue, colon, small intestine, biliary tract, gut, bone marrow,hematopoietic tissue, or eye (e.g., retinal) tissue.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe eye. In some embodiments, the fibrotic condition is glaucoma,macular degeneration (e.g., age-related macular degeneration), macularedema (e.g., diabetic macular edema), retinopathy (e.g., diabeticretinopathy), or dry eye disease.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung. In certain embodiments, the fibrotic condition of the lungis chosen from one or more of: pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lungdisease, cryptogenic fibrosing alveolitis (CFA), bronchiectasis, andscleroderma lung disease. In one embodiment, the fibrosis of the lung issecondary to a disease, a toxin, an insult, a medical treatment, or acombination thereof. For example, the fibrosis of the lung can beassociated with (e.g., secondary to) one or more of: a disease processsuch as asbestosis and silicosis; an occupational hazard; anenvironmental pollutant; cigarette smoking; an autoimmune connectivetissue disorders (e.g., rheumatoid arthritis, scleroderma and systemiclupus erythematosus (SLE)); a connective tissue disorder such assarcoidosis; an infectious disease, e.g., infection, particularlychronic infection; a medical treatment, including but not limited to,radiation therapy, and drug therapy, e.g., chemotherapy (e.g., treatmentwith as bleomycin, methotrexate, amiodarone, busulfan, and/ornitrofurantoin). In one embodiment, the fibrotic condition of the lungtreated with the methods provided herein is associated with (e.g.,secondary to) a cancer treatment, e.g., treatment of a cancer (e.g.,squamous cell carcinoma, testicular cancer, Hodgkin's disease withbleomycin). In one embodiment, the fibrotic condition of the lung isassociated with an autoimmune connective tissue disorder (e.g.,scleroderma or lupus, e.g., SLE).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the liver. In certain embodiments, the fibrotic condition of theliver is chosen from one or more of: fatty liver disease, steatosis(e.g., nonalcoholic steatohepatitis (NASH), cholestatic liver disease(e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol inducedliver fibrosis, biliary duct injury, biliary fibrosis, orcholangiopathies. In other embodiments, hepatic or liver fibrosisincludes, but is not limited to, hepatic fibrosis associated withalcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B orD), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD),progressive massive fibrosis, exposure to toxins or irritants (e.g.,alcohol, pharmaceutical drugs and environmental toxins).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the heart. In certain embodiments, the fibrotic condition of theheart is myocardial fibrosis (e.g., myocardial fibrosis associated withradiation myocarditis, a surgical procedure complication (e.g.,myocardial post-operative fibrosis), infectious diseases (e.g., Chagasdisease, bacterial, trichinosis or fungal myocarditis)); granulomatous,metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis);developmental disorders (e.g., endocardial fibroelastosis);arteriosclerotic, or exposure to toxins or irritants (e.g., drug inducedcardiomyopathy, drug induced cardiotoxicity, alcoholic cardiomyopathy,cobalt poisoning or exposure). In certain embodiments, the myocardialfibrosis is associated with an inflammatory disorder of cardiac tissue(e.g., myocardial sarcoidosis). In some embodiments, the fibroticcondition is a fibrotic condition associated with a myocardialinfarction. In some embodiments, the fibrotic condition is a fibroticcondition associated with congestive heart failure.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the kidney. In certain embodiments, the fibrotic condition of thekidney is chosen from one or more of: renal fibrosis (e.g., chronickidney fibrosis), nephropathies associated with injury/fibrosis (e.g.,chronic nephropathies associated with diabetes (e.g., diabeticnephropathy)), lupus, scleroderma of the kidney, glomerular nephritis,focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosisassociated with human chronic kidney disease (CKD), chronic progressivenephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction,chronic uremia, chronic interstitial nephritis, radiation nephropathy,glomerulosclerosis, progressive glomerulonephrosis (PGN),endothelial/thrombotic microangiopathy injury, HIV-associatednephropathy, or fibrosis associated with exposure to a toxin, anirritant, or a chemotherapeutic agent. In one embodiment, the fibroticcondition of the kidney is scleroderma of the kidney. In someembodiments, the fibrotic condition of the kidney is transplantnephropathy, diabetic nephropathy, lupus nephritis, or focal segmentalglomerulosclerosis (FSGS).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the skin. In certain embodiments, the fibrotic condition of the skinis chosen from one or more of: skin fibrosis (e.g., hypertrophicscarring, keloid), scleroderma, nephrogenic systemic fibrosis (e.g.,resulting after exposure to gadolinium (which is frequently used as acontrast substance for MRIs) in patients with severe kidney failure),and keloid.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the gastrointestinal tract. In certain embodiments, the fibroticcondition is chosen from one or more of: fibrosis associated withscleroderma; radiation induced gut fibrosis; fibrosis associated with aforegut inflammatory disorder such as Barrett's esophagus and chronicgastritis, and/or fibrosis associated with a hindgut inflammatorydisorder, such as inflammatory bowel disease (IBD), ulcerative colitisand Crohn's disease. In some embodiments, the fibrotic condition of thegastrointestinal tract is fibrosis associated with scleroderma.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the bone marrow or a hematopoietic tissue. In certain embodiments,the fibrotic condition of the bone marrow is an intrinsic feature of achronic myeloproliferative neoplasm of the bone marrow, such as primarymyelofibrosis (also referred to herein as agnogenic myeloid metaplasiaor chronic idiopathic myelofibrosis). In other embodiments, the bonemarrow fibrosis is associated with (e.g., is secondary to) a malignantcondition or a condition caused by a clonal proliferative disease. Inother embodiments, the bone marrow fibrosis is associated with ahematologic disorder (e.g., a hematologic disorder chosen from one ormore of polycythemia vera, essential thrombocythemia, myelodysplasia,hairy cell leukemia, lymphoma (e.g., Hodgkin or non-Hodgkin lymphoma),multiple myeloma or chronic myelogeneous leukemia (CML)). In yet otherembodiments, the bone marrow fibrosis is associated with (e.g.,secondary to) a non-hematologic disorder (e.g., a non-hematologicdisorder chosen from solid tumor metastasis to bone marrow, anautoimmune disorder (e.g., systemic lupus erythematosus, scleroderma,mixed connective tissue disorder, or polymyositis), an infection (e.g.,tuberculosis), or secondary hyperparathyroidism associated with vitaminD deficiency. In some embodiments, the fibrotic condition is idiopathicor drug-induced myelofibrosis. In some embodiments, the fibroticcondition of the bone marrow or hematopoietic tissue is associated withsystemic lupus erythematosus or scleroderma.

In one embodiment, provided herein is a method of treating, preventingand/or managing scleroderma. Scleroderma is a group of diseases thatinvolve hardening and tightening of the skin and/or other connectivetissues. Scleroderma may be localized (e.g., affecting only the skin) orsystemic (e.g., affecting other systems such as, e.g., blood vesselsand/or internal organs). Common symptoms of scleroderma includeRaynaud's phenomenon, gastroesophageal reflux disease, and skin changes(e.g., swollen fingers and hands, or thickened patches of skin). In someembodiments, the scleroderma is localized, e.g., morphea or linearscleroderma. In some embodiments, the condition is a systemic sclerosis,e.g., limited systemic sclerosis, diffuse systemic sclerosis, orsystemic sclerosis sine scleroderma.

Localized scleroderma (localized cutaneous fibrosis) includes morpheaand linear scleroderma. Morphea is typically characterized byoval-shaped thickened patches of skin that are white in the middle, witha purple border. Linear scleroderma is more common in children. Symptomsof linear scleroderma may appear mostly on one side of the body. Inlinear scleroderma, bands or streaks of hardened skin may develop on oneor both arms or legs or on the forehead. En coup de sabre (frontallinear scleroderma or morphea en coup de sabre) is a type of localizedscleroderma typically characterized by linear lesions of the scalp orface.

Systemic scleroderma (systemic sclerosis) includes, e.g., limitedsystemic sclerosis (also known as limited cutaneous systemic sclerosis,or CREST syndrome), diffuse systemic sclerosis (also known as diffusecutaneous systemic sclerosis), and systemic sclerosis sine scleroderma.CREST stands for the following complications that may accompany limitedscleroderma: calcinosis (e.g., of the digits), Raynaud's phenomenon,esophageal dysfunction, sclerodactyly, and telangiectasias. Typically,limited scleroderma involves cutaneous manifestations that mainly affectthe hands, arms, and face. Limited and diffuse subtypes aredistinguished based on the extent of skin involvement, with sparing ofthe proximal limbs and trunk in limited disease. See, e.g., Denton, C.P. et al. (2006), Nature Clinical Practice Rheumatology, 2(3):134-143.The limited subtype also typically involves a long previous history ofRaynaud's phenomenon, whereas in the diffuse subtype, onset of Raynaud'sphenomenon can be simultaneous with other manifestations or might occurlater. Both limited and diffuse subtypes may involve internal organs.Typical visceral manifestations of limited systemic sclerosis includeisolated pulmonary hypertension, severe bowel involvement, and pulmonaryfibrosis. Typical visceral manifestations of diffuse systemic sclerosisinclude renal crisis, lung fibrosis, and cardiac disease. Diffusesystemic sclerosis typically progresses rapidly and affects a large areaof the skin and one or more internal organs (e.g., kidneys, esophagus,heart, or lungs). Systemic sclerosis sine scleroderma is a rare disorderin which patients develop vascular and fibrotic damage to internalorgans in the absence of cutaneous sclerosis.

In one embodiment, provided herein is a method of treating, preventingand/or managing inflammatory myopathies. As used herein, “inflammatorymyopathies” encompass all types and manifestations of inflammatorymyopathies. Examples include, but are not limited to, muscle weakness(e.g., proximal muscle weakness), skin rash, fatigue after walking orstanding, tripping or falling, dysphagia, dysphonia, difficultybreathing, muscle pain, tender muscles, weight loss, low-grade fever,inflamed lungs, light sensitivity, calcium deposits (calcinosis) underthe skin or in the muscle, as well as biological concomitants ofinflammatory myopathies as disclosed herein or as known in the art.Biological concomitants of inflammatory myopathies (e.g.,dermatomyositis) include, e.g., altered (e.g., increased) levels ofcytokines (e.g., Type I interferons (e.g., IFN-α and/or IFN-β),interleukins (e.g., IL-6, IL-10, IL-15, IL-17 and IL-18), and TNF-α),TGF-β, B-cell activating factor (BAFF), overexpression of IFN induciblegenes (e.g., Type I IFN inducible genes). Other biological concomitantsof inflammatory myopathies can include, e.g., an increased erythrocytesedimentation rate (ESR) and/or elevated level of creatine kinaseFurther biological concomitants of inflammatory myopathies can includeautoantibodies, e.g., anti-synthetase autoantibodies (e.g., anti-Jo1antibodies), anti-signal recognition particle antibodies (anti-SRP),anti-Mi-2 antibodies, anti-p155 antibodies, anti-PM/Sci antibodies, andanti-RNP antibodies.

The inflammatory myopathy can be an acute inflammatory myopathy or achronic inflammatory myopathy. In some embodiments, the inflammatorymyopathy is a chronic inflammatory myopathy (e.g., dermatomyositis,polymyositis, or inclusion body myositis). In some embodiments, theinflammatory myopathy is caused by an allergic reaction, another disease(e.g., cancer or a connective tissue disease), exposure to a toxicsubstance, a medicine, or an infectious agent (e.g., a virus). In someembodiments, the inflammatory myopathy is associated with lupus,rheumatoid arthritis, or systemic sclerosis. In some embodiments, theinflammatory myopathy is idiopathic. In some embodiments, theinflammatory myopathy is selected from polymyositis, dermatomyositis,inclusion body myositis, and immune-mediated necrotizing myopathy. Insome embodiments, the inflammatory myopathy is dermatomyositis.

In another embodiment, provided herein is a method of treating,preventing and/or managing a skin condition (e.g., a dermatitis). Insome embodiments, the methods provided herein can reduce symptomsassociated with a skin condition (e.g., itchiness and/or inflammation).In some such embodiments, the compound provided herein is administeredtopically (e.g., as a topical cream, eye-drop, nose drop or nasalspray). In some such embodiments, the compound is a PI3K delta inhibitor(e.g., a PI3K inhibitor that demonstrates greater inhibition of PI3Kdelta than of other PI3K isoforms). In some embodiments, the PI3K deltainhibitor prevents mast cell degranulation.

As used herein, “skin condition” includes any inflammatory condition ofthe skin (e.g., eczema or dermatitis, e.g., contact dermatitis, atopicdermatitis, dermatitis herpetiformis, seborrheic dermatitis, nummulardermatitis, stasis dermatitis, perioral dermatitis), as well asaccompanying symptoms (e.g., skin rash, itchiness (pruritis), swelling(edema), hay fever, anaphalaxis). Frequently, such skin conditions arecaused by an allergen. As used herein, a “skin condition” also includes,e.g., skin rashes (e.g., allergic rashes, e.g., rashes resulting fromexposure to allergens such as poison ivy, poison oak, or poison sumac,or rashes caused by other diseases or conditions), insect bites, minorburns, sunburn, minor cuts, and scrapes. In some embodiments, thesymptom associated with inflammatory myopathy, or the skin condition orsymptom associated with the skin condition, is a skin rash or itchiness(pruritis) caused by a skin rash.

The skin condition (e.g., the skin rash) may be spontaneous, or it maybe induced, e.g., by exposure to an allergen (e.g., poison ivy, poisonoak, or poison sumac), drugs, food, insect bite, inhalants, emotionalstress, exposure to heat, exposure to cold, or exercise. In someembodiments, the skin condition is a skin rash (e.g., a pruritic rash,e.g., utricaria). In some embodiments, the skin condition is an insectbite. In some embodiments, the skin condition is associated with anotherdisease (e.g., an inflammatory myopathy, e.g., dermatomyositis).

In some embodiments, the subject (e.g., the subject in need of treatmentfor an inflammatory myopathy and/or a skin condition) exhibits anelevated level or elevated activity of IFN-α, TNF-α, IL-6, IL-8, IL-1,or a combination thereof. In certain embodiments, the subject exhibitsan elevated level of IFN-α. In some embodiments, treating (e.g.,decreasing or inhibiting) the inflammatory myopathy, or the skincondition, comprises inhibiting (e.g., decreasing a level of, ordecreasing a biological activity of) one or more of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α in the subjector in a sample derived from the subject. In some embodiments, the levelof IFN-α, TNF-α, IL-6, IL-8, or IL-1 is the level assessed in a sampleof whole blood or PBMCs. In some embodiments, the level of IFN-α, TNF-α,IL-6, IL-8, or IL-1 is the level assessed in a sample obtained by a skinbiopsy or a muscle biopsy. In some embodiments, the sample is obtainedby a skin biopsy.

In one embodiment, provided herein is a method of treating, preventingand/or managing myositis. As used herein, “myositis” encompasses alltypes and manifestations of myositis. Examples include, but are notlimited to, myositis ossificans, fibromyositis, idiopathic inflammatorymyopathies, dermatomyositis, juvenile dermatomyositis, polymyositis,inclusion body myositis and pyomyositis. In one embodiment, the diseaseor disorder is dermatomyositis. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith myositis. Examples of the symptoms include, but are not limited to:muscle weakness; trouble lifting arms; trouble swallowing or breathing;muscle pain; muscle tenderness; fatigue; fever; lung problems;gastrointestinal ulcers; intestinal perforations; calcinosis under theskin; soreness; arthritis; weight loss; and rashes.

In one embodiment, provided herein is a method of treating, preventingand/or managing lupus. As used herein, “lupus” refers to all types andmanifestations of lupus. Examples include, but are not limited to,systemic lupus erythematosus; lupus nephritis; cutaneous manifestations(e g , manifestations seen in cutaneous lupus erythematosus, e.g., askin lesion or rash); CNS lupus; cardiovascular, pulmonary, hepatic,hematological, gastrointestinal and musculoskeletal manifestations;neonatal lupus erythematosus; childhood systemic lupus erythematosus;drug-induced lupus erythematosus; anti-phospholipid syndrome; andcomplement deficiency syndromes resulting in lupus manifestations. Inone embodiment, the lupus is systemic lupus erythematosus (SLE),cutaneous lupus erythematosus (CLE), drug-induced lupus, or neonatallupus. In another embodiment, the lupus is a CLE, e.g., acute cutaneouslupus erythematosus (ACLE), subacute cutaneous lupus erythematosus(SCLE), intermittent cutaneous lupus erythematosus (also known as lupuserythematosus tumidus (LET)), or chronic cutaneous lupus. In someembodiments, the intermittent CLE is chronic discloid lupuserythematosus (CDLE) or lupus erythematosus profundus (LEP) (also knownas lupus erythematosus panniculitis). Types, symptoms, and pathogenesisof CLE are described, for example, in Wenzel et al. (2010), Lupus, 19,1020-1028.

In one embodiment, provided herein is a method of treating, preventingand/or managing Sjögren's syndrome. As used herein, “Sjögren's syndrome”refers to all types and manifestations of Sjögren's syndrome. Examplesinclude, but are not limited to, primary and secondary Sjögren'ssyndrome. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with Sjögren's syndrome.Examples of the symptoms include, but are not limited to: dry eyes; drymouth; joint pain; swelling; stiffness; swollen salivary glands; skinrashes; dry skin; vaginal dryness; persistent dry cough; and prolongedfatigue.

In some embodiments, a symptom associated with the disease or disorderprovided herein is reduced by at least 10%, at least 20%, at least 30%,at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95% relative to a control level. The controllevel includes any appropriate control as known in the art. For example,the control level can be the pre-treatment level in the sample orsubject treated, or it can be the level in a control population (e.g.,the level in subjects who do not have the disease or disorder or thelevel in samples derived from subjects who do not have the disease ordisorder). In some embodiments, the decrease is statisticallysignificant, for example, as assessed using an appropriate parametric ornon-parametric statistical comparison.

Combination Therapy

In some embodiments, provided herein are methods for combinationtherapies in which an agent known to modulate other pathways, or othercomponents of the same pathway, or even overlapping sets of targetenzymes are used in combination with a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. In one aspect, such therapy includes, but is notlimited to, the combination of the subject compound withchemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

By “in combination with,” it is not intended to imply that the othertherapy and the PI3K modulator must be administered at the same timeand/or formulated for delivery together, although these methods ofdelivery are within the scope of this disclosure. The compound providedherein can be administered concurrently with, prior to (e.g., 5 minutes,15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours,12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeksbefore), or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, 12 weeks, or 16 weeks after), one or more othertherapies (e.g., one or more other additional agents). In general, eachtherapeutic agent will be administered at a dose and/or on a timeschedule determined for that particular agent. The other therapeuticagent can be administered with the compound provided herein in a singlecomposition or separately in a different composition. Triple therapy isalso contemplated herein.

In general, it is expected that additional therapeutic agents employedin combination be utilized at levels that do not exceed the levels atwhich they are utilized individually. In some embodiments, the levelsutilized in combination will be lower than those utilized individually.

In some embodiments, the compound provided herein is a first linetreatment for cancer or hematologic malignancy, i.e., it is used in asubject who has not been previously administered another drug or therapyintended to treat cancer or hematologic malignancy or one or moresymptoms thereof.

In other embodiments, the compound provided herein is a second linetreatment for cancer or hematologic malignancy, i.e., it is used in asubject who has been previously administered another drug or therapyintended to treat cancer or hematologic malignancy or one or moresymptoms thereof.

In other embodiments, the compound provided herein is a third or fourthline treatment for cancer or hematologic malignancy, i.e., it is used ina subject who has been previously administered two or three other drugsor therapies intended to treat cancer or hematologic malignancy or oneor more symptoms thereof.

In embodiments where two agents are administered, the agents can beadministered in any order. For example, the two agents can beadministered concurrently (i.e., essentially at the same time, or withinthe same treatment) or sequentially (i.e., one immediately following theother, or alternatively, with a gap in between administration of thetwo). In some embodiments, the compound provided herein is administeredsequentially (i.e., after the first therapeutic).

In one aspect, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can presentsynergistic or additive efficacy when administered in combination withagents that inhibit IgE production or activity. Such combination canreduce the undesired effect of high level of IgE associated with the useof one or more PI3K-δ inhibitors, if such effect occurs. This can beparticularly useful in treatment of autoimmune and inflammatorydisorders (AIID) such as rheumatoid arthritis. Additionally, theadministration of PI3K-δ, PI3K-γ, or PI3K-δ/γ inhibitors as providedherein in combination with inhibitors of mTOR can also exhibit synergythrough enhanced inhibition of the PI3K pathway.

In a separate but related aspect, provided herein is a combinationtreatment of a disease associated with PI3K-δ comprising administeringto a subject in need thereof a PI3K-δ inhibitor and an agent thatinhibits IgE production or activity. Other exemplary PI3K-δ inhibitorsare applicable for this combination and they are described in, e.g.,U.S. Pat. No. 6,800,620, incorporated herein by reference. Suchcombination treatment is particularly useful for treating autoimmune andinflammatory diseases (AIID) including, but not limited to rheumatoidarthritis.

Agents that inhibit IgE production are known in the art and theyinclude, but are not limited to, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

For treatment of autoimmune diseases, a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, can be used in combination with commonly prescribed drugsincluding, but not limited to, Enbrel®, Remicade®, Humira®, Avonex®, andRebif®. For treatment of respiratory diseases, the subject compounds, orpharmaceutically acceptable forms thereof, or pharmaceuticalcompositions, can be administered in combination with commonlyprescribed drugs including, but not limited to, Xolair®, Advair®,Singulair®, and Spiriva®.

The compounds as provided herein, or pharmaceutically acceptable forms(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be formulated oradministered in conjunction with other agents that act to relieve thesymptoms of inflammatory conditions such as encephalomyelitis, asthma,and the other diseases described herein. These agents includenon-steroidal anti-inflammatory drugs (NSAIDs), e.g., acetylsalicylicacid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc.Corticosteroids are used to reduce inflammation and suppress activity ofthe immune system. An exemplary drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) can also be usedin some individuals with lupus. They can be prescribed for skin andjoint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide(Cytoxan) suppress inflammation and tend to suppress the immune system.Other agents, e.g., methotrexate and cyclosporin are used to control thesymptoms of lupus. Anticoagulants are employed to prevent blood fromclotting rapidly. They range from aspirin at very low dose whichprevents platelets from sticking, to heparin/coumadin. Other compoundsused in the treatment of lupus include belimumab (Benlysta®).

In another aspect, provided herein is a pharmaceutical composition forinhibiting abnormal cell growth in a subject which comprises an amountof a compound provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, in combinationwith an amount of an anti-cancer agent (e.g., a chemotherapeutic agent).Many chemotherapeutics are presently known in the art and can be used incombination with a compound provided herein.

In some embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib),Casodex™ (bicalutamide), Iressa® (gefitinib), Tarceva® (erlotinib), andAdriamycin® (doxorubicin) as well as a host of chemotherapeutic agents.Non-limiting examples of chemotherapeutic agents include alkylatingagents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphoramide andtrimethylolomelamine; BTK inhibitors such as ibrutinib (PCI-32765),AVL-292, Dasatinib, LFM-AI3, ONO-WG-307, and GDC-0834; HDAC inhibitorssuch as vorinostat, romidepsin, panobinostat, valproic acid, belinostat,mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat,CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215 andkevetrin; EZH2 inhibitors such as, but not limited to, EPZ-6438(N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide),GSK-126((S)-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide),GSK-343(1-Isopropyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(2-(4-methylpiperazin-1-yl)pyridine-4-yl)-1H-indazole-4-carboxamide),E, 3-deazaneplanocin A (DNNep, 5R-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-cyclopentene-1S,2R-diol), smallinterfering RNA (siRNA) duplexes targeted against EZH2 (S. M. Elbashiret al., Nature 411:494-498 (2001)), isoliquiritigenin, and thoseprovided in, for example, U.S. Publication Nos. 2009/0012031,2009/0203010, 2010/0222420, 2011/0251216, 2011/0286990, 2012/0014962,2012/0071418, 2013/0040906, and 2013/0195843, all of which areincorporated herein by reference; JAK/STAT inhibitors such aslestaurtinib, tofacitinib, ruxolitinib, pacritinib, CYT387, baricitinib,GLPG0636, TG101348, INCB16562, CP-690550, and AZD1480; PKC-β inhibitorsuch as Enzastaurin; SYK inhibitors such as, but not limited to,GS-9973, R788 (fostamatinib), PRT 062607, R406,(S)-2-(2-((3,5-dimethylphenyl)amino)pyrimidin-4-yl)-N-(1-hydroxypropan-2-yl)-4-methylthiazole-5-carboxamide,R112, GSK143, BAY61-3606, PP2, PRT 060318, R348, and those provided in,for example, U.S. Publication Nos. 2003/0113828, 2003/0158195,2003/0229090, 2005/0075306, 2005/0232969, 2005/0267059, 2006/0205731,2006/0247262, 2007/0219152, 2007/0219195, 2008/0114024, 2009/0171089,2009/0306214, 2010/0048567, 2010/0152159, 2010/0152182, 2010/0316649,2011/0053897, 2011/0112098, 2011/0245205, 2011/0275655, 2012/0027834,2012/0093913, 2012/0101275, 2012/0130073, 2012/0142671, 2012/0184526,2012/0220582, 2012/0277192, 2012/0309735, 2013/0040984, 2013/0090309,2013/0116260, and 2013/0165431, all of which are incorporated herein byreference; SYK/JAK dual inhibitor such as PRT2070; nitrogen mustardssuch as bendamustine, chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomycins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, porfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pralatrexate, pteropterin, trimetrexate; purine analogssuch as fludambine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine;demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (Am-C); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (e.g., TAXOL™) and docetaxel (e.g., TAXOTERE™) and ABRAXANE®(paclitaxel protein-bound particles); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) of any of the above.Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO). Where desired, the compounds orpharmaceutical composition as provided herein can be used in combinationwith commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®,Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE,abagovomab, acridine carboxamide, adecatumumab,17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib,3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide,anthracenedione, anti-CD22 immunotoxins, antineoplastic, antitumorigenicherbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine,BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine,CBV (chemotherapy), calyculin, crizotinib, cell-cycle nonspecificantineoplastic agents, dichloroacetic acid, discodermolide,elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan,exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen,IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar,larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide,mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1,pawpaw, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod,rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V,swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel,triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine,uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

In some embodiments, the chemotherapeutic is selected from hedgehoginhibitors including, but not limited to IPI-926 (See U.S. Pat. No.7,812,164). Other suitable hedgehog inhibitors include, for example,those described and disclosed in U.S. Pat. No. 7,230,004, U.S. PatentApplication Publication No. 2008/0293754, U.S. Patent ApplicationPublication No. 2008/0287420, and U.S. Patent Application PublicationNo. 2008/0293755, the entire disclosures of which are incorporated byreference herein. Examples of other suitable hedgehog inhibitors includethose described in U.S. Patent Application Publication Nos. US2002/0006931, US 2007/0021493 and US 2007/0060546, and InternationalApplication Publication Nos. WO 2001/19800, WO 2001/26644, WO2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354, each incorporated herein by reference. Additional examplesof hedgehog inhibitors include, but are not limited to, GDC-0449 (alsoknown as RG3616 or vismodegib) described in, e.g., Von Hoff D. et al.,N. Engl. J. Med. 2009; 361(12):1164-72; Robarge K. D. et al., Bioorg MedChem Lett. 2009; 19(19):5576-81; Yauch, R. L. et al. (2009) Science 326:572-574; Sciencexpress: 1-3 (10.1126/science.1179386); Rudin, C. et al.(2009) New England J of Medicine 361-366 (10.1056/nejma0902903);BMS-833923 (also known as XL139) described in, e.g., in Siu L. et al.,J. Clin. Oncol. 2010; 28:15s (suppl; abstr 2501); and National Instituteof Health Clinical Trial Identifier No. NCT006701891; LDE-225 described,e.g., in Pan S. et al., ACS Med. Chem. Lett., 2010; 1(3): 130-134;LEQ-506 described, e.g., in National Institute of Health Clinical TrialIdentifier No. NCT01106508; PF-04449913 described, e.g., in NationalInstitute of Health Clinical Trial Identifier No. NCT00953758; Hedgehogpathway antagonists disclosed in U.S. Patent Application Publication No.2010/0286114; SMOi2-17 described, e.g., U.S. Patent ApplicationPublication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., inRominger C. M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005;1-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med. Chem. Lett. 2010; 20(12):3618-22.

Other hormonal therapy and chemotherapeutic agents include, but are notlimited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrolacetate), LHRH agonists (e.g. goserelin and leuprolide), anti-androgens(e.g. flutamide and bicalutamide), photodynamic therapies (e.g.vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, anddemethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g.cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine,and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine(CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes(e.g. dacarbazine, temozolomide), platinum containing compounds (e.g.cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine,vinblastine, vindesine, and vinorelbine), taxoids or taxanes (e.g.paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-boundpaclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel(DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel(PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), thetumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to threemolecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to theerbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel,e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel,taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine,doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C, cytosine arabinoside), andfludarabine), purine analogs (e.g. mercaptopurine and thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracyclines(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin),thalidomide, lenalidomide (REVLIMID®), tyrosine kinase inhibitors (e.g.,axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), sorafenib (NEXAVAR®), everolimus(AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®),temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate(TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903,PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120(VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbazine, prednisolone,dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immuno-stimulants and/or immuno-modulatory agents (e.g.,IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar(tositumomab), or Perjeta (pertuzumab)).

In one embodiment, the biotherapeutic agent is an anti-CD37 antibodysuch as, but not limited to, IMGN529, K7153A and TRU-016. In anotherembodiment, the biotherapeutic agent is an anti-CD20 antibody such as,but not limited to, ¹³¹I tositumomab, ⁹⁰Y ibritumomab, ¹¹¹I ibritumomab,obinutuzumab and ofatumumab. In another embodiment, the biotherapeuticagent is an anti-CD52 antibody such as, but not limited to, alemtuzumab.

In some embodiments, the chemotherapeutic is selected from HSP90inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g.,a benzoquinone or hygroquinone ansamycin HSP90 inhibitor (e.g., IPI-493and/or IPI-504). Non-limiting examples of HSP90 inhibitors includeIPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010),BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009),SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG,CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159,CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3Kinhibitors (e.g., including those PI3K inhibitors provided herein andthose PI3K inhibitors not provided herein). In some embodiment, the PI3Kinhibitor is an inhibitor of delta and gamma isoforms of PI3K. In someembodiment, the PI3K inhibitor is an inhibitor of delta isoform of PI3K.In some embodiment, the PI3K inhibitor is an inhibitor of gamma isoformof PI3K. In some embodiments, the PI3K inhibitor is an inhibitor ofalpha isoform of PI3K. In other embodiments, the PI3K inhibitor is aninhibitor of one or more alpha, beta, delta and gamma isoforms of PI3K.Exemplary PI3K inhibitors that can be used in combination are describedin, e.g., WO 09/088990, WO 09/088086, WO 2011/008302, WO 2010/036380, WO2010/006086, WO 09/114870, WO 05/113556; US 2009/0312310, and US2011/0046165, each incorporated herein by reference. Additional PI3Kinhibitors that can be used in combination with the pharmaceuticalcompositions, include but are not limited to, AMG-319, GSK 2126458,GDC-0980, GDC-0941, Sanofi XL147, XL499, XL756, XL147, PF-4691502, BKM120, CAL-101 (GS-1101), CAL 263, SF1126, PX-886, and a dual PI3Kinhibitor (e.g., Novartis BEZ235). In one embodiment, the PI3K inhibitoris an isoquinolinone.

In one embodiment, the PI3K gamma selective compound selectivelyinhibits PI3K gamma isoform over PI3K delta isoform. In one embodiment,the PI3K gamma selective compound has a delta/gamma selectivity ratio ofgreater than 1, greater than about 5, greater than about 10, greaterthan about 50, greater than about 100, greater than about 200, greaterthan about 400, greater than about 600, greater than about 800, greaterthan about 1000, greater than about 1500, greater than about 2000,greater than about 5000, greater than about 10,000, or greater thanabout 20,000. In one embodiment, the PI3K gamma selective compound has adelta/gamma selectivity ratio in the range of from greater than 1 toabout 5, from about 5 to about 10, from about 10 to about 50, from about50 to about 850, or greater than about 850. In one embodiment, thedelta/gamma selectivity ratio is determined by dividing the compound'sIC₅₀ against PI3K delta isoform by the compound's IC₅₀ against PI3Kgamma isoform.

In one embodiment, the PI3K delta selective compound selectivelyinhibits PI3K delta isoform over PI3K gamma isoform. In one embodiment,the PI3K delta selective compound has a gamma/delta selectivity ratio ofgreater than 1, greater than about 5, greater than about 10, greaterthan about 50, greater than about 100, greater than about 200, greaterthan about 400, greater than about 600, greater than about 800, greaterthan about 1000, greater than about 1500, greater than about 2000,greater than about 5000, greater than about 10,000, or greater thanabout 20,000. In one embodiment, the PI3K delta selective compound has agamma/delta selectivity ratio in the range of from greater than 1 toabout 5, from about 5 to about 10, from about 10 to about 50, from about50 to about 850, or greater than about 850. In one embodiment, thegamma/delta selectivity ratio is determined by dividing the inhibitor'sIC₅₀ against PI3K gamma isoform by the inhibitor's IC₅₀ against PI3Kdelta isoform.

In certain embodiments, the PI3K inhibitor is a PI3K delta selectivecompound. In one embodiment, the PI3K delta selective compoundselectively inhibits PI3K delta isoform over PI3K alpha isoform. In oneembodiment, the PI3K delta selective compound has an alpha/deltaselectivity ratio of greater than 1, greater than about 5, greater thanabout 10, greater than about 50, greater than about 100, greater thanabout 200, greater than about 400, greater than about 600, greater thanabout 800, greater than about 1000, greater than about 1500, greaterthan about 2000, greater than about 5000, greater than about 10,000, orgreater than about 20,000. In one embodiment, the PI3K delta selectivecompound has an alpha/delta selectivity ratio in the range of fromgreater than 1 to about 5, from about 5 to about 10, from about 10 toabout 50, from about 50 to about 850, or greater than about 850. In oneembodiment, the alpha/delta selectivity ratio is determined by dividingthe inhibitor's IC₅₀ against PI3K alpha isoform by the inhibitor's IC₅₀against PI3K delta isoform.

In certain embodiments, the PI3K inhibitor is a PI3K delta selectivecompound. In one embodiment, the PI3K delta selective compoundselectively inhibits PI3K delta isoform over PI3K beta isoform. In oneembodiment, the PI3K delta selective compound has a beta/deltaselectivity ratio of greater than 1, greater than about 5, greater thanabout 10, greater than about 50, greater than about 100, greater thanabout 200, greater than about 400, greater than about 600, greater thanabout 800, greater than about 1000, greater than about 1500, greaterthan about 2000, greater than about 5000, greater than about 10,000, orgreater than about 20,000. In one embodiment, the PI3K delta selectivecompound has a beta/delta selectivity ratio in the range of from greaterthan 1 to about 5, from about 5 to about 10, from about 10 to about 50,from about 50 to about 850, or greater than about 850. In oneembodiment, the beta/delta selectivity ratio is determined by dividingthe compound's IC₅₀ against PI3K beta isoform by the compound's IC₅₀against PI3K delta isoform.

In one embodiment, the PI3K delta selective compound is GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),or AMG319, or a mixture thereof. In one embodiment, the PI3K deltaselective compound is GS1101.

In some embodiments, provided herein is a method for using a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the subject. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of acompound provided herein in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation, external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner as provided herein include both solids and liquids. Byway of non-limiting example, the radiation source can be a radionuclide,such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solidsource, or other radionuclides that emit photons, beta particles, gammaradiation, or other therapeutic rays. The radioactive material can alsobe a fluid made from any solution of radionuclide(s), e.g., a solutionof I-125 or I-131, or a radioactive fluid can be produced using a slurryof a suitable fluid containing small particles of solid radionuclides,such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in agel or radioactive micro spheres.

Without being limited by any theory, a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, provided herein is a method for sensitizing abnormalcells in a subject to treatment with radiation which comprisesadministering to the subject an amount of a compound provided herein, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, which amount is effective in sensitizing abnormalcells to treatment with radiation. The amount of the compound used inthis method can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

In one embodiment, a compound as provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can be usedin combination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Other therapeutic agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound provided herein, or a pharmaceutically acceptable form thereof,or a pharmaceutical composition described herein. Such therapeuticagents include, for example, rapamycin, temsirolimus (CCI-779),everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples ofuseful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, androfecoxib. Examples of useful matrix metalloproteinase inhibitors aredescribed in WO 96/33172 (published Oct. 24, 1996), WO 96/27583(published Mar. 7, 1996), European Patent Application No. 97304971.1(filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filedOct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516(published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6,1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931, 788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 31, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. PCT/IB98/01113 (filed Jul. 21, 1998),European Patent Application No. 99302232.1 (filed Mar. 25, 1999), GreatBritain Patent Application No. 9912961.1 (filed Jun. 3, 1999), U.S.Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat.No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issuedJan. 19, 1999), and European Patent Publication 780,386 (published Jun.25, 1997), all of which are incorporated herein in their entireties byreference. In some embodiments, MMP-2 and MMP-9 inhibitors are thosethat have little or no activity inhibiting MMP-1. Other embodimentsinclude those that selectively inhibit MMP-2 and/or AMP-9 relative tothe other matrix-metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5,MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Somenon-limiting examples of MMP inhibitors are AG-3340, RO 32-3555, and RS13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNAs that inhibit expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

In some embodiments, provided herein is a method of and/or apharmaceutical composition for treating a cardiovascular disease in asubject which comprises an amount of a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, and an amount of one or more therapeutic agentsuse for the treatment of cardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings. Moreover, a coating can be used to effect therapeutic deliveryfocally within the vessel wall. By incorporation of the active agent ina swellable polymer, the active agent will be released upon swelling ofthe polymer.

In one embodiment, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can beformulated or administered in conjunction with liquid or solid tissuebarriers also known as lubricants. Examples of tissue barriers include,but are not limited to, polysaccharides, polyglycans, seprafilm,interceed and hyaluronic acid.

Medicaments which can be administered in conjunction with a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, include anysuitable drugs usefully delivered by inhalation for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g. cromoglycate,ketotifen or nedocromil; anti-infectives, e.g., cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments can be usedin the form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) to optimize theactivity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude, but are not limited to, agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemic,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated herein include drugs used forcontrol of gastric acidity, agents for the treatment of peptic ulcers,agents for the treatment of gastroesophageal reflux disease, prokineticagents, antiemetics, agents used in irritable bowel syndrome, agentsused for diarrhea, agents used for constipation, agents used forinflammatory bowel disease, agents used for biliary disease, agents usedfor pancreatic disease. Therapeutic agents include, but are not limitedto, those used to treat protozoan infections, drugs used to treatMalaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/orLeishmaniasis, and/or drugs used in the chemotherapy of helminthiasis.Other therapeutic agents include, but are not limited to, antimicrobialagents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, andagents for urinary tract infections, penicillins, cephalosporins, andother, β-Lactam antibiotics, an agent containing an aminoglycoside,protein synthesis inhibitors, drugs used in the chemotherapy oftuberculosis, mycobacterium avium complex disease, and leprosy,antifungal agents, antiviral agents including nonretroviral agents andantiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundprovided herein include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immuno-modulation, such asimmuno-modulators, immuno-suppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and anti-platelet drugs are alsocontemplated by the methods herein.

In exemplary embodiments, for treating renal carcinoma, one can combinea compound provided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, with sorafenib and/oravastin. For treating an endometrial disorder, one can combine acompound provided herein with doxorubincin, taxotere (taxol), and/orcisplatin (carboplatin). For treating ovarian cancer, one can combine acompound provided herein with cisplatin, carboplatin, docetaxel,doxorubincin, topotecan, and/or tamoxifen. For treating breast cancer,one can combine a compound provided herein with paclitaxel or docetaxel,gemcitabine, capecitabine, tamoxifen, letrozole, erlotinib, lapatinib,PD0325901, bevacizumab, trastuzumab, OSI-906, and/or OSI-930. Fortreating lung cancer, one can combine a compound as provided herein withpaclitaxel, docetaxel, gemcitabine, cisplatin, pemetrexed, erlotinib,PD0325901, and/or bevacizumab

In some embodiments, the disorder to be treated, prevented and/ormanaged is a hematological cancer, e.g., lymphoma (e.g., T-celllymphoma; NHL), myeloma (e.g., multiple myeloma), and leukemia (e.g.,CLL), and a compound provided herein is used in combination with: HDACinhibitors such as vorinostat, romidepsin and ACY-1215; mTOR inhibitorssuch as everolimus; anti-folates such as pralatrexate; nitrogen mustardsuch as bendamustine; gemcitabine, optionally in further combinationwith oxaliplatin; rituximab-cyclophosphamide combination; PI3Kinhibitors such as GS-1101, XL 499, GDC-0941, and AMG-319; angiogenesisinhibitors such as pomalidomide or BTK inhibitors such as ibrutinib,AVL-292, Dasatinib, LFM-AI3, ONO-WG-307, and GDC-0834. In someembodiments, the disorder to be treated, prevented and/or managed isDLBCL, and a compound provided herein, or a pharmaceutically acceptablederivative (e.g., salt or solvate) thereof, is used in combination withHDAC inhibitors provided herein. In one particular embodiment, the HDACinhibitor is ACY-1215.

In some embodiments, the disorder to be treated, prevented and/ormanaged is DLBCL, and a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with BTK inhibitors provided herein. In one particularembodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTKinhibitor is AVL-292.

In some embodiments, the disorder to be treated, prevented and/ormanaged is DLBCL, and a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with IRAK inhibitors provided herein. In one particularembodiment, the IRAK4 inhibitor is ND-2110 or ND-2158.

In some embodiments, the disorder to be treated, prevented and/ormanaged is WM, and a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with BTK inhibitors provided herein. In one particularembodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTKinhibitor is AVL-292.

In some embodiments, the disorder to be treated, prevented and/ormanaged is WM, and a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with IRAK4 inhibitors provided herein. In one particularembodiment, the IRAK4 inhibitor is ND-2110 or ND-2158.

In some embodiments, the disorder to be treated, prevented and/ormanaged is T-ALL, the subject/patient has a PTEN deficiency, and acompound provided herein, or a pharmaceutically acceptable derivative(e.g., salt or solvate) thereof, is used in combination with doxorubicinand/or vincristine.

In certain embodiments, wherein inflammation (e.g., arthritis, asthma)is treated, prevented and/or managed, a compound provided herein can becombined with, for example: PI3K inhibitors such as GS-1101, XL 499,GDC-0941, and AMG-319; BTK inhibitors such as ibrutinib and AVL-292; JAKinhibitors such as tofacitinib, fostamatinib, and GLPG0636.

In certain embodiments wherein asthma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:beta 2-agonists such as, but not limited to, albuterol (Proventil®, orVentolin®), salmeterol (Serevent®), formoterol (Foradil®),metaproterenol (Alupent®), pirbuterol (MaxAir®), and terbutalinesulfate; corticosteroids such as, but not limited to, budesonide (e.g.,Pulmicort®), flunisolide (e.g., AeroBid Oral Aerosol Inhaler® orNasalide Nasal Aerosol®), fluticasone (e.g., Flonase® or Flovent®) andtriamcinolone (e.g., Azmacort®); mast cell stabilizers such as cromolynsodium (e.g., Intal® or Nasalcrom®) and nedocromil (e.g., Tilade®);xanthine derivatives such as, but not limited to, theophylline (e.g.,Aminophyllin®, Theo-24® or Theolair®); leukotriene receptor antagonistssuch as, but are not limited to, zafirlukast (Accolate®), montelukast(Singulair®), and zileuton (Zyflo®); and adrenergic agonists such as,but are not limited to, epinephrine (Adrenalin®, Bronitin®, EpiPen® orPrimatene Mist®).

In certain embodiments wherein arthritis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:TNF antagonist (e.g., a TNF antibody or fragment, a soluble TNF receptoror fragment, fusion proteins thereof, or a small molecule TNFantagonist); other biologic antirhheumatics (e.g., IL-6 antagonists,IL-1 antagonists, costimulatory modulators); an antirheumatic (e.g.,methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, goldsodium thiomalate, chrloroquine, hydroxychloroquine sulfate,leflunomide, sulfasalzine, penicillamine); a muscle relaxant; anarcotic; a non-steroid anti-inflammatory drug (NSAID); an analgesic; ananesthetic; a sedative; a local anesthetic; a neuromuscular blocker; anantimicrobial (e.g., an aminoglycoside, an antifungal, an antiparasitic,an antiviral, a carbapenem, cephalosporin, a fluoroquinolone, amacrolide, a penicillin, a sulfonamide, a tetracycline, anotherantimicrobial); an antipsoriatic; a corticosteroid; an anabolic steroid;a cytokine or a cytokine antagonist; a calcineurin inhibitor (e.g.,cyclosporine, tacrolimus).

In some embodiments, a compound provided herein, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof) isadministered in combination with an agent for the treatment ofrheumatoid arthritis. Examples of agents for the treatment of rheumatoidarthritis include, but are not limited to, various NSAIDs,corticosteroids, sulfasalazine, auranofin, methotrexate, azathioprine,penicillamine, cyclosporine, Arava (leflunomide), TNF inhibitors (e.g.,Enbrel (etanercept), Remicade (infliximab), Humira (adalimumab), Simponi(golimumab), and Cimzia (certolizumab)), IL-1 inhibitors (e.g., Kineret(anakinra)), T-cell costimulatory modulators (e.g., Orencia(abatacept)), Anti-CD20 (e.g., Rituxan (rituximab)), and IL-6 inhibitors(e.g., Actemra (tocilizumab)). In one embodiment, the agent is Cimzia(certolizumab). In another embodiment, the agent is Actemra(tocilizumab).

In some embodiments, a compound provided herein, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof) isadministered in combination with an agent for rheumatology. Examples ofagents for rheumatology include, but are not limited to, Rayos(prednisone), Stendra (avanafil), Actemra (tocilizumab), Duexis(ibuprofen and famotidine), Actemra (tocilizumab), Krystexxa(pegloticase), Vimovo (naproxen+esomeprazole), Cimzia (certolizumabpegol), Colcrys (colchicine), Pennsaid (diclofenac sodium topicalsolution), Simponi (golimumab), Uloric (febuxostat), Orencia(abatacept), Elaprase (idursulfase), Orencia (abatacept), Vioxx(rofecoxib), Enbrel (etanercept), Humira (adalimumab), Remicade(infliximab), Bextra, Kineret, Remicade (infliximab), Supartz, Mobic(meloxicam), Vivelle (estradiol transdermal system), Lodine XL(etodolac), Arava, Salagen, Arthrotec, Etodolac, Ketoprofen, Synvisc,Tolmetin Sodium, Azulfidine EN-tabs Tablets (sulfasalazine delayedrelease tablets, USP), and Naprelan (naproxen sodium).

In some embodiments, the second agent is selected from belimumab,AGS-009, rontalizumab, vitamin D3, sifalimumab, AMG 811, IFNα Kinoid,CEP33457, epratuzumab, LY2127399, Ocrelizumab, Atacicept, A-623,SBI-087, AMG557, laquinimod, rapamycin, cyclophosphamide, azathioprine,mycophenolate, leflunomide, methotrexate, CNTO 136, tamibarotene,N-acetylcysteine, CDP7657, hydroxychloroquine, rituximab, carfilzomib,bortezomib, ONX 0914, IMO-3100, DV1179, sulfasalazine, and chloroquine.In one embodiment, the second agent is methotrexate, sulfasalazine,chloroquine, or hydroxychloroquine. In one embodiment, the second agentis methotrexate.

In certain embodiments wherein psoriasis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:budesonide, epidermal growth factor, corticosteroids, cyclosporine,sulfasalazine, aminosalicylates, 6-mercaptopurine, azathioprine,metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine,balsalazide, antioxidants, thromboxane inhibitors, IL-1 receptorantagonists, anti-IL-1β monoclonal antibodies, anti-IL-6 monoclonalantibodies, growth factors, elastase inhibitors, pyridinyl-imidazolecompounds, antibodies or agonists of TNF, LT, IL-1, IL-2, IL-6, IL-7,IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies ofCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, prednisolone,phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents,complement inhibitors, adrenergic agents, IRAK, NIK, IKK, p38, MAPkinase inhibitors, IL-1β converting enzyme inhibitors, TNFα convertingenzyme inhibitors, T-cell signaling inhibitors, metalloproteinaseinhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensinconverting enzyme inhibitors, soluble cytokine receptors, soluble p55TNF receptor, soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R,anti-inflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and TGFβ.

In certain embodiments wherein fibrosis or fibrotic condition of thebone marrow is treated, prevented and/or managed, a compound providedherein can be combined with, for example, a Jak2 inhibitor (including,but not limited to, INCB018424, XL019, TG101348, or TG101209), animmuno-modulator, e.g., an IMID® (including, but not limited tothalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen,erythropoietic stimulating agents, prednisone, danazol, HDAC inhibitors,or other agents or therapeutic modalities (e.g., stem cell transplants,or radiation).

In certain embodiments wherein fibrosis or fibrotic condition of theheart is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, eplerenone, furosemide, pycnogenol,spironolactone, TcNC100692, torasemide (e.g., prolonged release form oftorasemide), or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thekidney is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, cyclosporine, cyclosporine A,daclizumab, everolimus, gadofoveset trisodium (ABLAVAR®), imatinibmesylate (GLEEVEC®), matinib mesylate, methotrexate, mycophenolatemofetil, prednisone, sirolimus, spironolactone, STX-100, tamoxifen,TheraCLEC™, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theskin is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, Bosentan (Tracleer), p144,pentoxifylline; pirfenidone; pravastatin, STI571, Vitamin E, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thegastrointestinal system is treated, prevented and/or managed, a compoundprovided herein can be combined with, for example, ALTU-135, bucelipasealfa (INN), DCI1020, EUR-1008 (ZENPEP™), ibuprofen, Lym-X-Sorb powder,pancrease MT, pancrelipase (e.g., pancrelipase delayed release), pentadecanoic acid (PA), repaglinide, TheraCLEC™, triheptadecanoin (THA),ULTRASE MT20, ursodiol, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thelung is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, 18-FDG, AB0024, ACT-064992(macitentan), aerosol interferon-gamma, aerosolized human plasma-derivedalpha-1 antitrypsin, alpha1-proteinase inhibitor, ambrisentan, amikacin,amiloride, amitriptyline, anti-pseudomonas IgY gargle, ARIKACE™,AUREXIS® (tefibazumab), AZAPRED, azathioprine, azithromycin,azithromycin, AZLI, aztreonam lysine, BIBF1120, Bio-25 probiotic,bosentan, Bramitob®, calfactant aerosol, captopril, CC-930, ceftazidime,ceftazidime, cholecalciferol (Vitamin D3), ciprofloxacin (CIPRO®,BAYQ3939), CNTO 888, colistin CF, combined Plasma Exchange (PEX),rituximab, and corticosteroids, cyclophosphamide, dapsone, dasatinib,denufosol tetrasodium (INS37217), dornase alfa (PULMOZYME®), EPI-hNE4,erythromycin, etanercept, FG-3019, fluticasone, FTI, GC1008, GS-9411,hypertonic saline, ibuprofen, iloprost inhalation, imatinib mesylate(GLEEVEC®), inhaled sodium bicarbonate, inhaled sodium pyruvate,interferon gamma-1b, interferon-alpha lozenges, isotonic saline, IW001,KB001, losartan, lucinactant, mannitol, meropenem, meropenem infusion,miglustat, minocycline, Moli1901, MP-376 (levofloxacin solution forinhalation), mucoid exopolysaccharide P. aeruginosa immune globulin IV,mycophenolate mofetil, n-acetylcysteine, N-acetylcysteine (NAC), NaCl6%, nitric oxide for inhalation, obramycin, octreotide, oligoG CF-5/20,Omalizumab, pioglitazone, piperacillin-tazobactam, pirfenidone,pomalidomide (CC-4047), prednisone, prevastatin, PRM-151, QAX576,rhDNAse, SB656933, SB-656933-AAA, sildenafil, tamoxifen, technetium[Tc-99m] sulfur colloid and Indium [In-111] DTPA, tetrathiomolybdate,thalidomide, ticarcillin-clavulanate, tiotropium bromide, tiotropiumRESPIMAT® inhaler, tobramycin (GERNEBCIN®), treprostinil, uridine,valganciclovir (VALCYTE®), vardenafil, vitamin D3, xylitol, zileuton, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theliver is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, adefovir dipivoxil, candesartan,colchicine, combined ATG, mycophenolate mofetil, and tacrolimus,combined cyclosporine microemulsion and tacrolimus, elastometry,everolimus, FG-3019, Fuzheng Huayu, GI262570, glycyrrhizin (monoammoniumglycyrrhizinate, glycine, L-cysteine monohydrochloride), interferongamma-1b, irbesartan, losartan, oltipraz, ORAL IMPACT®, peginterferonalfa-2a, combined peginterferon alfa-2a and ribavirin, peginterferonalfa-2b (SCH 54031), combined peginterferon alpha-2b and ribavirin,praziquantel, prazosin, raltegravir, ribavirin (REBETOL®, SCH 18908),ritonavir-boosted protease inhibitor, pentoxyphilline, tacrolimus,tauroursodeoxycholic acid, tocopherol, ursodiol, warfarin, orcombinations thereof.

In certain embodiments wherein cystic fibrosis is treated, preventedand/or managed, a compound provided herein can be combined with, forexample, 552-02, 5-methyltetrahydrofolate and vitamin B12, Ad5-CB-CFTR,Adeno-associated virus-CFTR vector, albuterol, alendronate, alphatocopherol plus ascorbic acid, amiloride HCl, aquADEK™, ataluren(PTC124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin(clarithromycin), BIIL 283 BS (amelubent), buprofen, calcium carbonate,ceftazidime, cholecalciferol, choline supplementation, CPX, cysticfibrosis transmembrane conductance regulator, DHA-rich supplement,digitoxin, cocosahexaenoic acid (DHA), doxycycline, ECGC, ecombinanthuman IGF-1, educed glutathione sodium salt, ergocalciferol (vitaminD2), fluorometholone, gadobutrol (GADOVIST®, BAY86-4875), gentamicin,ghrelin, glargine, glutamine, growth hormone, GS-9411, H5.001CBCFTR,human recombinant growth hormone, hydroxychloroquine, hyperbaric oxygen,hypertonic saline, IH636 grape seed proanthocyanidin extract, insulin,interferon gamma-1b, IoGen (molecular iodine), iosartan potassium,isotonic saline, itraconazole, IV gallium nitrate (GANITE®) infusion,ketorolac acetate, lansoprazole, L-arginine, linezolid, lubiprostone,meropenem, miglustat, MP-376 (levofloxacin solution for inhalation),normal saline IV, Nutropin AQ, omega-3 triglycerides, pGM169/GL67A,pGT-1 gene lipid complex, pioglitazone, PTC124, QAU145, salmeterol,SB656933, SB656933, simvastatin, sitagliptin, sodium 4-phenylbutyrate,standardized turmeric root extract, tgAAVCF, TNF blocker, TOBI,tobramycin, tocotrienol, unconjugated Isoflavones 100, vitamin: cholinebitartrate (2-hydroxyethyl) trimethylammonium salt 1:1, VX-770, VX-809,Zinc acetate, or combinations thereof.

In some embodiments, a compound provided herein is administered incombination with an agent that inhibits IgE production or activity. Insome embodiments, the PI3K inhibitor (e.g., PI3Kδ inhibitor) isadministered in combination with an inhibitor of mTOR. Agents thatinhibit IgE production are known in the art and they include but are notlimited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

In certain embodiments wherein scleroderma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:an immunosuppressant (e.g., methotrexate, azathioprine (Imuran®),cyclosporine, mycophenolate mofetil (Cellcept®), and cyclophosphamide(Cytoxan®)); T-cell-directed therapy (e.g., halofuginone, basiliximab,alemtuzumab, abatacept, rapamycin); B-cell directed therapy (e.g.,rituximab); autologous hematopoietic stem cell transplantation; achemokine ligand receptor antagonist (e.g., an agent that targets theCXCL12/CSCR4 axis (e.g., AMD3100)); a DNA methylation inhibitor (e.g.,5-azacytidine); a histone deacetylase inhibitor (e.g., trichostatin A);a statin (e.g., atorvastatin, simvastatin, pravastatin); an endothelinreceptor antagonist (e.g., Bosentan®); a phosphodiesterase type Vinhibitor (e.g., Sildenafil®); a prostacyclin analog (e.g.,trepostinil); an inhibitor of cytokine synthesis and/or signaling (e g.,Imatinib mesylate, Rosiglitazone, rapamycin, antitransforming growthfactor β1 (anti-TGFβ1) antibody, mycophenolate mofetil, an anti-IL-6antibody (e.g., tocilizumab)); corticosteroids; nonsteroidalanti-inflammatory drugs; light therapy; and blood pressure medications(e.g., ACE inhibitors).

In certain embodiments wherein inflammatory myopathies are treated,prevented and/or managed, a compound provided herein can be combinedwith, for example: topical creams or ointments (e.g., topicalcorticosteroids, tacrolimus, pimecrolimus); cyclosporine (e.g., topicalcyclosporine); an anti-interferon therapy, e.g., AGS-009, Rontalizumab(rhuMAb IFNalpha), Vitamin D3, Sifalimumab (MEDI-545), AMG 811, IFNαKinoid, or CEP33457. In some embodiments, the other therapy is an IFN-αtherapy, e.g., AGS-009, Rontalizumab, Vitamin D3, Sifalimumab (MEDI-545)or IFNα Kinoid; corticosteroids such as prednisone (e.g., oralprednisone); immunosuppressive therapies such as methotrexate (Trexall®,Methotrexate®, Rheumatrex®), azathioprine (Azasant, Imuran®),intravenous immunoglobulin, tacrolimus (Prograf®), pimecrolimus,cyclophosphamide (Cytoxan®), and cyclosporine (Gengraf®, Neoral®,Sandimmune®); anti-malarial agents such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®); total body irradiation;rituximab (Rituxan®); TNF inhibitors (e.g., etanercept (Enbrel®),infliximab (Remicade®)); AGS-009; Rontalizumab (rhuMAb IFNalpha);Vitamin D3; Sifalimumab (MEDI-545); AMG 811; IFNα Kinoid,; CEP33457;agents that inhibit IgE production such as TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2;agents that inhibit IgE activity such as anti-IgE antibodies (e.g.,Omalizumab and TNX-90); and additional therapies such as physicaltherapy, exercise, rest, speech therapy, sun avoidance, heat therapy,and surgery.

In certain embodiments wherein myositis (e.g., dermatomysitis) istreated, prevented and/or managed, a compound provided herein can becombined with, for example: corticosteroids; corticosteroid sparingagents such as, but not limited to, azathioprine and methotrexate;intravenous immunoglobulin; immunosuppressive agents such as, but notlimited to, tacrolimus, cyclophosphamide and cyclosporine; rituximab;TNFα inhibitors such as, but not limited to, etanercept and infliximab;growth hormone; growth hormone secretagogues such as, but not limitedto, MK-0677, L-162752, L-163022, NN703 ipamorelin, hexarelin, GPA-748(KP102, GHRP-2), and LY444711 (Eli Lilly); other growth hormone releasestimulators such as, but not limited to, Geref, GHRH (1-44), Somatorelin(GRF 1-44), ThGRF genotropin, L-DOPA, glucagon, and vasopressin; andinsulin-like growth factor.

In certain embodiments wherein Sjögren's syndrome is treated, preventedand/or managed, a compound provided herein can be combined with, forexample: pilocarpine; cevimeline; nonsteroidal anti-inflammatory drugs;arthritis medications; antifungal agents; cyclosporine;hydroxychloroquine; prednisone; azathioprine; and cyclophamide.

Further therapeutic agents that can be combined with a compound providedherein can be found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

In one embodiment, the compounds described herein can be used incombination with the agents provided herein or other suitable agents,depending on the condition being treated. Hence, in some embodiments, acompound provided herein, or a pharmaceutically acceptable form thereof,will be co-administered with other agents as described above. When usedin combination therapy, a compound described herein, or apharmaceutically acceptable form thereof, can be administered with asecond agent simultaneously or separately. This administration incombination can include simultaneous administration of the two agents inthe same dosage form, simultaneous administration in separate dosageforms, and separate administration. That is, a compound described hereinand any of the agents described above can be formulated together in thesame dosage form and administered simultaneously. Alternatively, acompound provided herein and any of the agents described above can besimultaneously administered, wherein both agents are present in separateformulations. In another alternative, a compound provided herein can beadministered just followed by any of the agents described above, or viceversa. In the separate administration protocol, a compound providedherein and any of the agents described above can be administered a fewminutes apart, or a few hours apart, or a few days apart.

Administration of a compound provided herein, or a pharmaceuticallyacceptable form thereof, can be effected by any method that enablesdelivery of the compound to the site of action. An effective amount of acompound provided herein, or a pharmaceutically acceptable form thereof,can be administered in either single or multiple doses by any of theaccepted modes of administration of agents having similar utilities,including rectal, buccal, intranasal, and transdermal routes, byintra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, orally, topically, as aninhalant, or via an impregnated or coated device such as a stent, forexample, or an artery-inserted cylindrical polymer.

When a compound provided herein, or a pharmaceutically acceptable formthereof, is administered in a pharmaceutical composition that comprisesone or more agents, and the agent has a shorter half-life than thecompound provided herein, unit dose forms of the agent and the compoundas provided herein can be adjusted accordingly.

In some embodiments, the compound provided herein and the second agentare administered as separate compositions, e.g., pharmaceuticalcompositions. In some embodiments, the PI3K modulator and the agent areadministered separately, but via the same route (e.g., both orally orboth intravenously). In other embodiments, the PI3K modulator and theagent are administered in the same composition, e.g., pharmaceuticalcomposition.

In some embodiments, a compound provided herein, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof) isadministered in combination with an agent for pulmonary or respiratorydiseases. Examples of agents for pulmonary or respiratory diseasesinclude, but are not limited to, Dymista (azelastine hydrochloride andfluticasone propionate), Kalydeco (ivacaftor), Qnasl (beclomethasonedipropionate) nasal aerosol, Rayos (prednisone) delayed-release tablets,Surfaxin (lucinactant), Tudorza Pressair (aclidinium bromide inhalationpowder), Arcapta (indacaterol maleate inhalation powder), Daliresp(roflumilast), Xalkori (crizotinib), Cayston (aztreonam for inhalationsolution), Dulera (mometasone furoate+formoterol fumarate dihydrate),Teflaro (ceftaroline fosamil), Adcirca (tadalafil), Tyvaso(treprostinil), Alvesco (ciclesonide), Patanase (olopatadinehydrochloride), Letairis (ambrisentan), Xyzal (levocetirizinedihydrochloride), Brovana (arformoterol tartrate), Tygacil(tigecycline), Ketek (telithromycin), Spiriva HandiHaler (tiotropiumbromide), Aldurazyme (laronidase), Iressa (gefitinib), Xolair(omalizumab), Zemaira (alphal-proteinase inhibitor), Clarinex, Qvar(beclomethasone dipropionate), Remodulin (treprostinil), Xopenex, AveloxI.V. (moxifloxacin hydrochloride), DuoNeb (albuterol sulfate andipratropium bromide), Foradil Aerolizer (formoterol fumarate inhalationpowder), Invanz, NasalCrom Nasal Spray, Tavist (clemastine fumarate),Tracleer (bosentan), Ventolin HFA (albuterol sulfate inhalationaerosol), Biaxin XL (clarithromycin extended-release tablets), Cefazolinand Dextrose USP, Tri-Nasal Spray (triamcinolone acetonide spray),Accolate, Cafcit Injection, Proventil HFA Inhalation Aerosol, RhinocortAqua Nasal Spray, Tequin, Tikosyn Capsules, Allegra-D, Clemastinefumarate syrup, Curosurf, Dynabac, Infasurf, Priftin, Pulmozyme (dornasealfa), Sclerosol Intrapleural Aerosol, Singulair, Synagis, Ceftin(cefuroxime axetil), Cipro (ciprofloxacin HCl), Claritin RediTabs (10 mgloratadine rapidly-disintegrating tablet), Flonase Nasal Spray, FloventRotadisk, Metaprotereol Sulfate Inhalation Solution (5%), Nasacort AQ(triamcinolone acetonide) Nasal Spray, Omnicef, Raxar (grepafloxacin),Serevent, Tilade (nedocromil sodium), Tobi, Vanceril 84 mcg DoubleStrength (beclomethasone dipropionate, 84 mcg) Inhalation Aerosol, Zagam(sparfloxacin) tablets, Zyflo (Zileuton), Accolate, Allegra(fexofenadine hydrochloride), Astelin nasal spray, Atrovent (ipratropiumbromide), Augmentin (amoxicillin/clavulanate), Azmacort (triamcinoloneacetonide) Inhalation Aerosol, Breathe Right, Claritin Syrup(loratadine), Claritin-D 24 Hour Extended Release Tablets (10 mgloratadine, 240 mg pseudoephedrine sulfate), Covera-HS (verapamil),Nasacort AQ (triamcinolone acetonide) Nasal Spray, OcuHist, Pulmozyme(dornase alfa), RespiGam (Respiratory Syncitial Virus Immune GlobulinIntravenous), Tavist (clemastine fumarate), Tripedia (Diptheria andTetanus Toxoids and Acellular Pertussis Vaccine Absorbed), Vancenase AQ84 mcg Double Strength, Visipaque (iodixanol), Zosyn (sterilepiperacillin sodium/tazobactam sodium), Cedax (ceftibuten), and Zyrtec(cetirizine HCl). In one embodiment, the agent for pulmonary orrespiratory diseases is Arcapta, Daliresp, Dulera, Alvesco, Brovana,Spiriva HandiHaler, Xolair, Qvar, Xopenex, DuoNeb, Foradil Aerolizer,Accolate, Singulair, Flovent Rotadisk, Tilade, Vanceril, Zyflo, orAzmacort Inhalation Aerosol. In one embodiment, the agent for pulmonaryor respiratory diseases is Spiriva HandiHaler.

In some embodiments, a compound provided herein, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof) isadministered in combination with an agent for immunology or infectiousdiseases. Examples of agents for immunology or infectious diseasesinclude, but are not limited to, Horizant (gabapentin enacarbil), Qnasl(beclomethasone dipropionate) nasal aerosol, Rayos (prednisone)delayed-release tablets, Stribild (elvitegravir, cobicistat,emtricitabine, tenofovir disoproxil fumarate), Tudorza Pressair(aclidinium bromide inhalation powder), Arcapta (indacaterol maleateinhalation powder), Benlysta (belimumab), Complera(emtricitabine/rilpivirine/tenofovir disoproxil fumarate), Daliresp(roflumilast), Dificid (fidaxomicin), Edurant (rilpivirine), Firazyr(icatibant), Gralise (gabapentin), Incivek (telaprevir), Nulojix(belatacept), Victrelis (boceprevir), Cayston (aztreonam for inhalationsolution), Egrifta (tesamorelin for injection), Menveo (meningitisvaccine), Oravig (miconazole), Prevnar 13 (Pneumococcal 13-valentConjugate Vaccine), Teflaro (ceftaroline fosamil), Zortress(everolimus), Zymaxid (gatifloxacin ophthalmic solution), Bepreve(bepotastine besilate ophthalmic solution), Berinert (Cl EsteraseInhibitor (Human)), Besivance (besifloxacin ophthalmic suspension),Cervarix [Human Papillomavirus Bivalent (Types 16 and 18) Vaccine,Recombinant], Coartem (artemether/lumefantrine), Hiberix (Haemophilus bConjugate Vaccine; Tetanus Toxoid Conjugate), Ilaris (canakinumab),Ixiaro (Japanese Encephalitis Vaccine, Inactivated, Adsorbed), Kalbitor(ecallantide), Qutenza (capsaicin), Vibativ (telavancin), Zirgan(ganciclovir ophthalmic gel), Aptivus (tipranavir), Astepro (azelastinehydrochloride nasal spray), Cinryze (Cl Inhibitor (Human)), Intelence(etravirine), Moxatag (amoxicillin), Rotarix (Rotavirus Vaccine, Live,Oral), Tysabri (natalizumab), Viread (tenofovir disoproxil fumarate),Altabax (retapamulin), AzaSite (azithromycin), Doribax (doripenem),Extina (ketoconazole), Isentress (raltegravir), Selzentry (maraviroc),Veramyst (fluticasone furoate), Xyzal (levocetirizine dihydrochloride),Eraxis (anidulafungin), Gardasil (quadrivalent human papillomavirus(types 6, 11, 16, 18) recombinant vaccine), Noxafil (posaconazole),Prezista (darunavir), Rotateq (rotavirus vaccine, live oralpentavalent), Tyzeka (telbivudine), Veregen (kunecatechins), Aptivus(tipranavir), Baraclude (entecavir), Tygacil (tigecycline), Ketek(telithromycin), Tindamax, tinidazole, Xifaxan (rifaximin), Amevive(alefacept), FluMist (Influenza Virus Vaccine), Fuzeon (enfuvirtide),Lexiva (fosamprenavir calcium), Reyataz (atazanavir sulfate), Alinia(nitazoxanide), Clarinex, Daptacel, Fluzone Preservative-free, Hepsera(adefovir dipivoxil), Pediarix Vaccine, Pegasys (peginterferon alfa-2a),Restasis (cyclosporine ophthalmic emulsion), Sustiva, Vfend(voriconazole), Avelox I.V. (moxifloxacin hydrochloride), Cancidas,Peg-Intron (peginterferon alfa-2b), Rebetol (ribavirin), Spectracef,Twinrix, Valcyte (valganciclovir HCl), Viread (tenofovir disoproxilfumarate), Xigris (drotrecogin alfa [activated]), ABREVA (docosanol),Biaxin XL (clarithromycin extended-release tablets), Cefazolin andDextrose USP, Children's Motrin Cold, Evoxac, Kaletra Capsules and OralSolution, Lamisil (terbinafine hydrochloride) Solution (1%), Lotrisone(clotrimazole/betamethasone diproprionate) lotion, Malarone (atovaquone;proguanil hydrochloride) Tablet, Rapamune (sirolimus) Tablets, RidMousse, Tri-Nasal Spray (triamcinolone acetonide spray), Trivagizole 3(clotrimazole) Vaginal Cream, Trizivir (abacavir sulfate; lamivudine;zidovudine AZT) Tablet, Agenerase (amprenavir), Cleocin (clindamycinphosphate), Famvir (famciclovir), Norvir (ritonavir), Panretin Gel,Rapamune (sirolimus) oral solution, Relenza, Synercid I.V., Tamiflucapsule, Vistide (cidofovir), Allegra-D, CellCept, Clemastine fumaratesyrup, Cleocin (clindamycin phosphate), Dynabac, REBETRON™ CombinationTherapy, Simulect, Timentin, Viroptic, INFANRIX (Diphtheria and TetanusToxoids and Acellular Pertussis Vaccine Adsorbed), Acyclovir Capsules,Aldara (imiquimod), Aphthasol, Combivir, Condylox Gel 0.5% (pokofilox),Famvir (famciclovir), Flagyl ER, Flonase Nasal Spray, Fortovase,INFERGEN (interferon alfacon-1), Intron A (interferon alfa-2b,recombinant), Norvir (ritonavir), Rescriptor Tablets (delavirdinemesylate tablets), SPORANOX (itraconazole), Stromectol (ivermectin),Taxol, Trovan, VIRACEPT (nelfinavir mesylate), Zerit (stavudine),Albenza (albendazole), Apthasol (Amlexanox), Carrington patch, Confide,Crixivan (Indinavir sulfate), Gastrocrom Oral Concentrate (cromolynsodium), Havrix, Lamisil (terbinafine hydrochloride) Tablets, Leukine(sargramostim), Oral Cytovene, RespiGam (Respiratory Syncitial VirusImmune Globulin Intravenous), Videx (didanosine), Viramune (nevirapine),Vistide (cidofovir), Vitrasert Implant, Zithromax (azithromycin), Cedax(ceftibuten), Clarithromycin (Biaxin), Epivir (lamivudine), Intron A(Interferon alfa-2b, recombinant), Invirase (saquinavir), Valtrex(valacyclovir HCl), Western blot confirmatory device, Zerit (stavudine),and Zyrtec (cetirizine HCl).

In some embodiments, the second agent is an HDAC inhibitor, such as,e.g., belinostat, vorinostat, panobinostat, ACY-1215, or romidepsin.

In some embodiments, the second agent is an mTOR inhibitor, such as,e.g., everolimus (RAD 001).

In some embodiments, the second agent is a proteasome inhibitor, suchas, e.g., bortezomib or carfilzomib.

In some embodiments, the second agent is a PKC-β inhibitor, such as,e.g., Enzastaurin (LY317615).

In some embodiments, the second agent is a JAK/STAT inhibitor, such as,e.g., INCB16562 or AZD 1480.

In some embodiments, the second agent is an anti-folate, such as, e.g.,pralatrexate.

In some embodiments, the second agent is a farnesyl transferaseinhibitor, such as, e.g., tipifarnib.

In some embodiments, the second agent is an antibody or a biologicagent, such as, e.g., alemtuzumab, rituximab, ofatumumab, or brentuximabvedotin (SGN-035). In one embodiment, the second agent is rituximab. Inone embodiment, the second agent is rituximab and the combinationtherapy is for treating, preventing, and/or managing iNHL, FL, splenicmarginal zone, nodal marginal zone, extranodal marginal zone, and/orSLL.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination bendamustine and one additional active agent. In oneembodiment, the cancer or hematological malignancy is iNHL.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination rituximab and one additional active agent. In oneembodiment, the cancer or hematological malignancy is iNHL.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination bendamustine and rituximab. In one embodiment, the cancer orhematological malignancy is iNHL.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination fludarabine, cyclophosphamide, and rituximab. In oneembodiment, the cancer or hematological malignancy is CLL.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with an antibody or a biologic agent, such as, e.g.,alemtuzumab, rituximab, ofatumumab, or brentuximab vedotin (SGN-035). Inone embodiment, the second agent is rituximab. In one embodiment, thesecond agent is rituximab and the combination therapy is for treating,preventing, and/or managing iNHL, FL, splenic marginal zone, nodalmarginal zone, extranodal marginal zone, and/or SLL.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with an antibody-drug conjugate, such as, e.g., inotuzumabozogamicin, or brentuximab vedotin.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with a cytotoxic agent, such as, e.g., bendamustine,gemcitabine, oxaliplatin, cyclophosphamide, vincristine, vinblastine,anthracycline (e.g., daunorubicin or daunomycin, doxorubicin),actinomycin, dactinomycin, bleomycin, clofarabine, nelarabine,cladribine, asparaginase, methotrexate, or pralatrexate.

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with one or more other anti-cancer agents orchemotherapeutic agents, such as, e.g., fludarabine, ibrutinib,fostamatinib, lenalidomide, thalidomide, rituximab, cyclophosphamide,doxorubicin, vincristine, prednisone, or R-CHOP (Rituximab,Cyclophosphamide, Doxorubicin or Hydroxydaunomycin, Vincristine orOncovin, Prednisone).

In some embodiments, a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, is used incombination with an antibody for a cytokine (e.g., an IL-15 antibody, anIL-21 antibody, an IL-4 antibody, an IL-7 antibody, an IL-2 antibody, anIL-9 antibody). In some embodiments, the second agent is a JAK1inhibitor, a JAK3 inhibitor, a pan-JAK inhibitor, a BTK inhibitor, anSYK inhibitor, or a PI3K delta inhibitor. In some embodiments, thesecond agent is an antibody for a chemokine.

Without being limited to a particular theory, a targeted combinationtherapy described herein has reduced side effect and/or enhancedefficacy. For example, in one embodiment, provided herein is acombination therapy for treating CLL with a compound described herein,or a pharmaceutically acceptable derivative (e.g., salt or solvate)thereof, and a second active agent (e.g., IL-15 antibodies, IL-21antibodies, IL-4 antibodies, IL-7 antibodies, IL-2 antibodies, IL-9antibodies, JAK1 inhibitors, JAK3 inhibitors, pan-JAK inhibitors, BTKinhibitors, SYK inhibitors, and/or PI3K delta inhibitors).

Further without being limited by a particular theory, it was found thata compound provided herein does not affect BTK or MEK pathway.Accordingly, in some embodiments, provided herein is a method oftreating or managing cancer or hematological malignancy comprisingadministering to a patient a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable derivative(e.g., salt or solvate) thereof, in combination with a BTK inhibitor. Inone embodiment, the BTK inhibitor is ibrutinib. In one embodiment, theBTK inhibitor is AVL-292. In one embodiment, the cancer or hematologicalmalignancy is DLBCL. In another embodiment, the cancer or hematologicalmalignancy is iNHL. In another embodiment, the cancer or hematologicalmalignancy is CLL.

In other embodiments, provided herein is a method of treating ormanaging cancer or hematological malignancy comprising administering toa patient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with a MEK inhibitor. In oneembodiment, the MEK inhibitor is trametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide),selumetinob(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyDamino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide),R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, RO4987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide),or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).In one embodiment, the cancer or hematological malignancy is DLBCL. Inanother embodiment, the cancer or hematological malignancy is ALL. Inanother embodiment, the cancer or hematological malignancy is CTCL.

In other embodiments, provided herein is a method of treating ormanaging cancer or hematological malignancy comprising administering toa patient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with an EZH2 inhibitor. In oneembodiment, the EZH2 inhibitor is EPZ-6438, GSK-126, GSK-343, E11, or3-deazaneplanocin A (DNNcp). In one embodiment, the cancer orhematological malignancy is DLBCL. In another embodiment, the cancer orhematological malignancy is iNHL. In another embodiment, the cancer orhematological malignancy is ALL. In another embodiment, the cancer orhematological malignancy is CTCL.

In other embodiments, provided herein is a method of treating ormanaging cancer or hematological malignancy comprising administering toa patient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with a bcl-2 inhibitor. In oneembodiment, the BCL2 inhibitor is ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide),ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), or G3139 (Oblimersen). In one embodiment, thecancer or hematological malignancy is DLBCL. In another embodiment, thecancer or hematological malignancy is iNHL. In another embodiment, thecancer or hematological malignancy is CLL. In another embodiment, thecancer or hematological malignancy is ALL. In another embodiment, thecancer or hematological malignancy is CTCL.

In other embodiments, provided herein is a method of treating ormanaging iNHL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith rituximab. In one embodiment, the patient is an elderly patient. Inanother embodiment, iNHL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging iNHL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith bendamustine. In one embodiment, iNHL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging iNHL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith rituximab, and in further combination with bendamustine. In oneembodiment, iNHL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging iNHL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith lenalidomide. In one embodiment, iNHL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging CLL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith rituximab. In one embodiment, the patient is an elderly patient. Inanother embodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging CLL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith bendamustine. In one embodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging CLL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith rituximab, and in further combination with bendamustine. In oneembodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging CLL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith lenalidomide. In one embodiment, CLL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging DLBCL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith rituximab. In one embodiment, the patient is an elderly patient. Inanother embodiment, DLBCL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging DLBCL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith bendamustine. In one embodiment, DLBCL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging DLBCL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith rituximab, and in further combination with bendamustine. In oneembodiment, DLBCL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging DLBCL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith R-GDP (rituximab, cyclophosphamide, vincristine and prednisone). Inone embodiment, DLBCL is relapsed or refractory. In another embodiment,the treatment is done subsequent to treatment by R-CHOP.

In other embodiments, provided herein is a method of treating ormanaging DLBCL comprising administering to a patient a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable derivative (e.g., salt or solvate) thereof, in combinationwith ibrutinib. In one embodiment, DLBCL is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging T-cell lymphoma (PTCL or CTCL) comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with rituximab. In one embodiment,T-cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging T-cell lymphoma (PTCL or CTCL) comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with bendamustine. In one embodiment,T-cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging T-cell lymphoma (PTCL or CTCL) comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with rituximab, and in furthercombination with bendamustine. In one embodiment, T-cell lymphoma isrelapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging T-cell lymphoma (PTCL or CTCL) comprising administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with romidepsin. In one embodiment,T-cell lymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging mantle cell lymphoma comprising administering to a patient atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable derivative (e.g., salt or solvate) thereof,in combination with rituximab. In one embodiment, mantle cell lymphomais relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging mantle cell lymphoma comprising administering to a patient atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable derivative (e.g., salt or solvate) thereof,in combination with bendamustine. In one embodiment, mantle celllymphoma is relapsed or refractory.

In other embodiments, provided herein is a method of treating ormanaging mantle cell lymphoma comprising administering to a patient atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable derivative (e.g., salt or solvate) thereof,in combination with rituximab, an din further combination withbendamustine. In one embodiment, mantle cell lymphoma is relapsed orrefractory.

In other embodiments, provided herein is a method of treating ormanaging mantle cell lymphoma comprising administering to a patient atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable derivative (e.g., salt or solvate) thereof,in combination with ibrutinib. In one embodiment, mantle cell lymphomais relapsed or refractory.

Further, without being limited by a particular theory, it was found thatcancer cells exhibit differential sensitivity profiles to doxorubicinand compounds provided herein. Thus, provided herein is a method oftreating or managing cancer or hematological malignancy comprisingadministering to a patient a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable derivative(e.g., salt or solvate) thereof, in combination with a doxorubicin. Inone embodiment, the cancer or hematological malignancy is ALL.

In some embodiments, provided herein is a method of treating or managingcancer or hematological malignancy comprising administering to a patienta therapeutically effective amount of a compound provided herein, or apharmaceutically acceptable derivative (e.g., salt or solvate) thereof,in combination with a AraC. In one embodiment, the cancer orhematological malignancy is AML.

In some embodiments, a compound provided herein or a pharmaceuticallyacceptable form thereof, is used in combination with one or more secondagent or second therapy provided herein.

In some embodiments, the second agent is an antibody-drug conjugate,such as, e.g., inotuzumab ozogamicin, or brentuximab vedotin.

In some embodiments, the second agent is a cytotoxic agent, such as,e.g., bendamustine, gemcitabine, oxaliplatin, cyclophosphamide,vincristine, vinblastine, anthracycline (e.g., daunorubicin ordaunomycin, doxorubicin), actinomycin, dactinomycin, bleomycin,clofarabine, nelarabine, cladribine, asparaginase, methotrexate, orpralatrexate.

In some embodiments, the second agent is one or more other anti-canceragents or chemotherapeutic agents, such as, e.g., fludarabine,ibrutinib, fostamatinib, lenalidomide, thalidomide, rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, or R-CHOP(Rituximab, Cyclophosphamide, Doxorubicin or Hydroxydaunomycin,Vincristine or Oncovin, Prednisone).

In some embodiments, the second agent is an antibody for a cytokine(e.g., an IL-15 antibody, an IL-21 antibody, an IL-4 antibody, an IL-7antibody, an IL-2 antibody, an IL-9 antibody). In some embodiments, thesecond agent is a JAK1 inhibitor, a JAK3 inhibitor, a pan-JAK inhibitor,a BTK inhibitor, an SYK inhibitor, or a PI3K delta inhibitor. In someembodiments, the second agent is an antibody for a chemokine.

Without being limited to a particular theory, a targeted combinationtherapy described herein has reduced side effect and/or enhancedefficacy. For example, in one embodiment, provided herein is acombination therapy for treating CLL with a compound described hereinand a second active agent (e.g., IL-15 antibodies, IL-21 antibodies,IL-4 antibodies, IL-7 antibodies, IL-2 antibodies, IL-9 antibodies, JAK1inhibitors, JAK3 inhibitors, pan-JAK inhibitors, BTK inhibitors, SYKinhibitors, and/or PI3K delta inhibitors).

Further without being limited by a particular theory, it was found thata compound provided herein does not affect BTK or MEK pathway.Accordingly, in some embodiments, provided herein is a method oftreating or managing cancer or hematological malignancy comprisingadministering to a patient a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable derivative(e.g., salt or solvate) thereof, in combination with a BTK inhibitor. Inone embodiment, the BTK inhibitor is ibrutinib. In one embodiment, theBTK inhibitor is AVL-292. In one embodiment, the cancer or hematologicalmalignancy is DLBCL. In another embodiment, the cancer or hematologicalmalignancy is CLL.

In other embodiments, provided herein is a method of treating ormanaging cancer or hematological malignancy comprising administering toa patient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with a MEK inhibitor. In oneembodiment, the MEK inhibitor is tametinib, selumetinob,AS703026/MSC1935369, XL-518/GDC-0973, BAY869766/RDEA119, GSK1120212(trametinib), pimasertib, refametinib, PD-0325901, TAK733,MEK162/ARRY438162, R05126766, WX-554, R04987655/CH4987655 or AZD8330. Inone embodiment, the cancer or hematological malignancy is DLBCL. Inanother embodiment, the cancer or hematological malignancy is ALL. Inanother embodiment, the cancer or hematological malignancy is CTCL.

In other embodiments, provided herein is a method of treating ormanaging cancer or hematological malignancy comprising administering toa patient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable derivative (e.g., salt orsolvate) thereof, in combination with a bcl-2 inhibitor. In oneembodiment, the BCL2 inhibitor is ABT-199, ABT-737, ABT-263, GX15-070(obatoclax mesylate) or G3139 (Genasense). In one embodiment, the canceror hematological malignancy is DLBCL. In another embodiment, the canceror hematological malignancy is ALL. In another embodiment, the cancer orhematological malignancy is CTCL.

Further, without being limited by a particular theory, it was found thatcancer cells exhibit differential sensitivity profiles to doxorubicinand compounds provided herein. Thus, provided herein is a method oftreating or managing cancer or hematological malignancy comprisingadministering to a patient a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable derivative(e.g., salt or solvate) thereof, in combination with a doxorubicin. Inone embodiment, the cancer or hematological malignancy is ALL.

Further provided herein are methods of modulating kinase activity bycontacting a kinase with an amount of a compound provided hereinsufficient to modulate the activity of the kinase Modulate can beinhibiting or activating kinase activity. In some embodiments, providedherein are methods of inhibiting kinase activity by contacting a kinasewith an amount of a compound provided herein sufficient to inhibit theactivity of the kinase In some embodiments, provided herein are methodsof inhibiting kinase activity in a solution by contacting said solutionwith an amount of a compound provided herein sufficient to inhibit theactivity of the kinase in said solution. In some embodiments, providedherein are methods of inhibiting kinase activity in a cell by contactingsaid cell with an amount of a compound provided herein sufficient toinhibit the activity of the kinase in said cell. In some embodiments,provided herein are methods of inhibiting kinase activity in a tissue bycontacting said tissue with an amount of a compound provided hereinsufficient to inhibit the activity of the kinase in said tissue. In someembodiments, provided herein are methods of inhibiting kinase activityin an organism by contacting said organism with an amount of a compoundprovided herein sufficient to inhibit the activity of the kinase in saidorganism In some embodiments, provided herein are methods of inhibitingkinase activity in an animal by contacting said animal with an amount ofa compound provided herein sufficient to inhibit the activity of thekinase in said animal. In some embodiments, provided herein are methodsof inhibiting kinase activity in a mammal by contacting said mammal withan amount of a compound provided herein sufficient to inhibit theactivity of the kinase in said mammal. In some embodiments, providedherein are methods of inhibiting kinase activity in a human bycontacting said human with an amount of a compound provided hereinsufficient to inhibit the activity of the kinase in said human. In someembodiments, the % of kinase activity after contacting a kinase with acompound provided herein is less than 1, 5, 10, 20, 30, 40, 50, 60, 70,80, 90, 95, or 99% of the kinase activity in the absence of saidcontacting step.

The examples and preparations provided below further illustrate andexemplify the compounds as provided herein and methods of preparing suchcompounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations. In the following examples molecules with asingle chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers can be obtained by methods known to thoseskilled in the art.

EXAMPLES Chemical Examples

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period that is, for example, about 1 to about24 hours; reactions left to run overnight in some embodiments canaverage a period of about 16 hours.

The terms “solvent,” “organic solvent,” and “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine, and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure, such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography, orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation proceduresare given by reference to the examples herein below. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the non-limiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer can besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation. Further, atropisomers (i.e.,stereoisomers from hindered rotation about single bonds) of compoundsprovided herein can be resolved or isolated by methods known to thoseskilled in the art.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In one embodiment, provided herein is a method of preparing a compoundprovided herein according to a procedure disclosed herein.

In some embodiments, compounds provided herein can generally besynthesized by an appropriate combination of generally well knownsynthetic methods. Techniques useful in synthesizing these chemicalentities are both readily apparent and accessible to those of skill inthe relevant art, based on the instant disclosure. Many of theoptionally substituted starting compounds and other reactants arecommercially available, e.g., from Aldrich Chemical Company (Milwaukee,Wis.) or can be readily prepared by those skilled in the art usingcommonly employed synthetic methodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the compounds and is not intended tolimit the scope of reactions or reaction sequences that can be used inpreparing the compounds provided herein.

General Synthetic Methods

The compounds herein being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodiments,and are not intended to limit these aspects and embodiments.

In one embodiment, compounds of Formula I′ provided herein can beprepared according to the scheme below:

Compound P1 can be treated with W_(d)—C(O)OH to afford compound P2,which can be treated with alkyne to generate a compound of Formula I′.Alternatively, Compound P1 can be treated with the alkyne first togenerate compound P3, which can be treated with W_(d)—C(O)OH to afford acompound of Formula I′.

(i) General Conditions for Amide Synthesis:

Method A:

To a mixture of amine P1 (Z is H) (0.5 mmol, 1.0 eq), W_(d)—COOHcarboxylic acid (0.55 mmol, 1.1 eq), and N,N-diisopropylethylamine (0.17mL, 1.0 mmol, 2.0 eq) in anhydrous DMF (5 mL), 1-hydroxybenzotriazolehydrate (0.65 mmol, 1.3 eq) and EDC hydrochloride (0.65 mmol, 1.3 eq)are added sequentially and the resulting mixture is stirred at RT for2-16 h. Ice-water or saturated sodium carbonate solution is added to thereaction mixture and then stirred for 10 min. The precipitate iscollected by filtration, rinsed with water and dried in vacuo. The solidcollected is further purified by flash column chromatography on silicagel (MeOH/DCM) or reverse phase HPLC (acetonitrile/water/formic acid) toafford the product amide P2.

Method B:

To a mixture of amine P1 (Z is H) (0.53 mmol, 1.0 equiv), W_(d)—COOHcarboxylic acid (0.58 mmol, 1.1 eq), and triethylamine (1.6 mmol) inanhydrous DMF (10 mL), 1-hydroxybenzotriazole (0.64 mmol, 1.2 equiv) andEDC hydrochloride (0.64 mmol, 1.2 eq) are added sequentially and theresulting mixture is stirred at 40° C. for 12 h. The mixture is thenconcentrated and purified using flash silica gel chromatography (10-100%ethyl acetate/petroleum ether) or reverse phase HPLC(acetonitrile/water/formic acid) to afford the product amide P2.

(ii) General Conditions for the Coupling of Alkyne to Aryl Halide:

Method C:

A sealed tube vessel is charged with PdCl₂(MeCN)₂ (16 mol %), X-Phos (50mol %), cesium carbonate (1.7 equiv) and propionitrile (3 mL). Themixture is stirred under Ar for 5 min after which compound P2 (0.36mmol, 1.0 equiv) is added in a solution of propionitrile (2 mL). Themixture is stirred under Ar for an additional 5 min after which alkynestarting material (1.7 equiv) is added in a solution of propionitrile (1mL). The mixture is sealed and stirred at room temperature for 10 minafter which it was heated to 95° C. for 4 h. The reaction is thenallowed to cool, diluted with methanol and filtered through a pad ofcelite. The filtrate is concentrated and purified using flash silica gelchromatography followed by further purification using flash silica gelchromatography or reverse phase HPLC (acetonitrile/water/formic acid) toprovide the compound of Formula I′.

Method D:

A mixture of compound P2 (0.45 mmol, 1.0 equiv), alkyne startingmaterial (2.0 equiv), Cs₂CO₃ (2.0 equiv), XPhos (50 mol %) andPd(dppf)Cl₂ (50 mol %) in dioxane (20 mL) is heated to 80-100° C. andstirred for 3 h after which the mixture is concentrated. The mixture ispurified by flash silica gel chromatography (MeOH/DCM) or reverse phaseHPLC (acetonitrile/water/formic acid) to provide the compound of FormulaI′.

(iii) General Conditions for Synthesis of Alkene Compounds of FormulaII′:

Method E:

To a mixture of alkyne compound of Formula I′ (0.12 mmol, 1.0 equiv)dissolved in a mixture of ethanol and ethyl acetate (20 mL, 3:1 v/v),palladium on carbon (10% Pd) is added and the reaction mixture is placedunder an atmosphere of H₂. The mixture is stirred at RT for 2 d afterwhich it is filtered through a filter disk, concentrated and purified byflash silica gel chromatography (methanol/methylene chloride) or reversephase HPLC (acetonitrile/water/formic acid) to provide the compound ofFormula II′ (one of R^(1a) is hydrogen).

Method F:

Compound P2 (0.22 mmol, 1.0 equiv), PdCl₂(Amphos)₂ (10 mol %) and sodiumcarbonate (2.0 equiv) are charged to a 4 mL vial under an Ar atmosphere.A solution of boronate starting material in dioxane/water (1.5 equiv, 2mL solvent, 4:1 v/v) is added and the reaction mixture is stirred at RTfor 5 min under Ar before heating to 85° C. for 1 h. The reaction isallowed to cool, diluted with methylene chloride (15 mL) and washed withwater (15 mL). The aqueous layer is then washed with additionalmethylene chloride (2×15 mL). The organic layers are combined and thenwashed with water (30 mL), brine (20 mL), dried over sodium sulfate andconcentrated to provide crude material which is first purified by flashsilica gel chromatography (methanol/methylene chloride) followed bypurification using reverse phase HPLC (acetonitrile/water/0.1% formicacid) provide the compound of Formula II′.

(iv) Synthesis of Core Structures:

Compounds with the moiety

can be synthesized based on the general procedures described in WO2015/051244. For example, they can be prepared according to the schemebelow.

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

To a stirred mixture of a given o-methylbenzoic acid (A-1) (1 eq, e.g.,1.5 mol) and DMF (catalytic, e.g., 2 mL) in DCM (1.2 M, e.g., 1275 mL)at RT, oxalyl chloride (1.1 eq, e.g., 1.65 mol) is added over 5 min andthe resulting mixture is stirred at RT for 2 h. The mixture is thenconcentrated in vacuo. The residue is dissolved in DCM (150 mL) and theresulting solution (solution A) is used directly in the next step.

To a stirred mixture of aniline (1.05 eq, e.g., 1.58 mol) andtriethylamine (2.1 eq, e.g., 3.15 mol) in DCM (1.2 M, e.g., 1350 mL),the above solution A (e.g., 150 mL) is added dropwise while the reactiontemperature is maintained between 25° C. to 40° C. by an ice-water bath.The resulting mixture is stirred at RT for 2 h and then water (e.g.,1000 mL) is added. The organic layers are separated and washed withwater (2× e.g., 1000 mL), dried over Na₂SO₄ and filtered. The filtrateis concentrated in vacuo. The product is suspended in n-heptanes (e.g.,1000 mL) and stirred at RT for 30 min. The precipitate is collected byfiltration, rinsed with heptanes (e.g., 500 mL) and further dried invacuo to afford the amide (A-2).

To a stirred mixture of amide (A-2) (1 eq, e.g., 173 mmol) in anhydrousTHF (e.g., 250 mL) at −30° C. under an argon atmosphere, a solution ofn-butyllithium in hexanes (2.5 eq, 2.5 M, e.g., 432 mol) is addeddropwise over 30 min while keeping the inner temperature between −30° C.and −10° C. The resulting mixture is then stirred at −30° C. for 30 min.

To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.5 eq, e.g., 260mmol) in anhydrous THF (e.g., 250 mL) at −30° C. under an argonatmosphere, a solution of isopropylmagnesium chloride in THF (1.65 eq, 1M, e.g., 286 mmol) is added dropwise over 30 min while keeping innertemperature between −30° C. and −10° C. The resulting mixture is stirredat −30° C. for 30 min. This solution is then slowly added to abovereaction mixture while keeping inner temperature between −30° C. and−10° C. The resulting mixture is stirred at −15° C. for 1 h. Thereaction mixture is quenched with water (e.g., 50 mL) and then acidifiedwith conc. HCl at −10° C. to 0° C. to adjust the pH to 1-3. The mixtureis allowed to warm to RT and concentrated in vacuo. The residue isdissolved in MeOH (e.g., 480 mL), and then conc. HCl (e.g., 240 mL) isadded quickly at RT. The resulting mixture is stirred at reflux for 1 h.The reaction mixture is concentrated in vacuo to reduce the volume toabout 450 mL. The residue is extracted with a 2:1 mixture of heptane andethyl acetate (e.g., 2×500 mL). The aqueous layer is basified withconcentrated ammonium hydroxide to adjust the pH value to 9-10 whilekeeping the inner temperature between −10° C. and 0° C. The mixture isthen extracted with DCM (e.g., 3×300 mL), washed with brine, dried overMgSO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is dissolved in MeOH (e.g., 1200 mL) at RT. To this solution,D-(−)-tartaric acid (0.8 eq, e.g., 21 g, 140 mmol) is added in oneportion at RT. After stirring at RT for 30 min, a white solidprecipitates and the mixture is slurried at RT for 10 h. The solid iscollected by filtration and rinsed with MeOH (e.g., 3×50 mL). Thecollected solid is suspended in water (e.g., 500 mL) and thenneutralized with concentrated ammonium hydroxide solution at RT toadjust the pH to 9-10. The mixture is extracted with DCM (e.g., 3×200mL). The combined organic layers are washed with brine, dried over MgSO₄and filtered. The filtrate is concentrated in vacuo to afford the(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones (A-3).

Compounds with the moiety

can be synthesized based on the general procedures described in WO2015/051244. For example, they can be prepared according to the schemebelow.

To a stirred mixture of nitrobenzoic acid (F-1) (1.0 eq, 1.0 mol) andDMF (e.g., 2.0 mL) in toluene (e.g., 800 mL), thionyl chloride (4.0 eq,e.g., 292 mL, 1.0 mol) is added dropwise (over 15 min) and the resultingmixture is stirred at reflux for 1.5 h. The mixture is allowed to coolto RT and then concentrated in vacuo. The residue is dissolved in DCM(e.g., 100 mL) to form solution A, which is used directly in the nextstep.

To a stirred mixture of a given amine R₂—NH₂ (1.1 eq, e.g., 102.4 g, 1.1mol) and triethylamine (2.0 eq, e.g., 280 mL, 2.0 mol) in DCM (1.6 M,e.g., 700 mL), solution A is added dropwise while keeping the reactiontemperature below 10° C. The resulting mixture is allowed to warm to RTand then stirred at RT overnight. The reaction mixture is diluted withice-water (e.g., 1.0 L) and stirred for 15 min. The precipitate iscollected by filtration, rinsed with isopropyl ether (e.g., 3×100 mL)and petroleum ether (e.g., 3×100 mL), and then dried in vacuo to affordproduct amide (F-2).

A mixture of nitro-benzamide (F-2) (1.0 eq, e.g., 20.0 mmol,) and DMF(cat.) in toluene (0.3 M, e.g., 60 mL) at RT, thionyl chloride (8.2 eq,e.g., 12 mL, 164 mmol) is added dropwise (over 5 min) and the resultingmixture is stirred at reflux for 2 h. The mixture is allowed to cool toRT and then concentrated in vacuo. The residue is dissolved in DCM(e.g., 10 mL) to form solution B, which is used directly in the nextstep.

To a stirred mixture of N-(tert-butoxycarbonyl)-L-alanine (0.8 eq, e.g.,16.0 mmol) and N,N-diisopropylethylamine (1.5 eq, e.g., 4.0 g, 31.0 mol)in DCM (0.8 M, e.g., 20 mL), solution B is added dropwise while keepingthe reaction temperature between 0-10° C. The resulting mixture isstirred at this temperature for 1 h and then stirred at RT overnight.The reaction mixture is quenched with ice-water (e.g., 100 mL). Theorganic layer is separated and the aqueous layer is extracted with DCM(e.g., 2×80 mL). The combined organic layers are washed with brine,dried over Na₂SO₄ and filtered. The filtrate is concentrated in vacuoand the residue is slurried in isopropyl ether (e.g., 100 mL) for 15min. The solid is collected by filtration and dried in vacuo to affordproduct (F-3).

To a suspension of zinc dust (10.0 eq, e.g., 7.2 g, 110 mmol) in glacialacetic acid (2.8 M, e.g., 40 mL) at 15° C., a solution of (F-3) (1.0 eq,e.g., 11.0 mmol) in glacial acetic acid (0.3 M, e.g., 40 mL) is addedand the resulting mixture is stirred at RT for 4 h. The mixture ispoured into ice-water (e.g., 200 mL) and neutralized with saturatedaqueous NaHCO₃ solution to adjust the pH to 8. The resulting mixture isextracted with DCM (e.g., 3×150 mL). The combined organic layers arewashed with brine, dried over Na₂SO₄ and filtered. The filtrate isconcentrated in vacuo and the residue is purified by flashchromatography on silica gel (7% ethyl acetate-petroleum ether) toafford product (F-4).

Compound (F-4) (1.0 eq, e.g., 0.5 mmol) is dissolved in hydrochloricmethanol solution (8 eq, e.g., 2N, 20 mL) and the resulting mixture isstirred at RT for 2 h. The mixture is concentrated in vacuo. The residueis diluted with water (30 mL) and then neutralized with saturatedaqueous NaHCO₃ to adjust the pH to 8 while keeping the temperature below5° C. The resulting mixture is extracted with DCM (e.g., 3×30 mL). Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue isslurried in petroleum ether (e.g., 10 mL). The solid is collected byfiltration and dried in vacuo to afford product (F-5).

Compounds with the moiety

can be synthesized based on the general procedures described inWO2014006572, WO2013164801, or WO2012151525. For example, they can beprepared according to the schemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2011008487, WO2010151735, Ferrarini et al., J. Het. Chem., 1999, 36,1123-1127, or Li et al., Bioorg. Med. Chem. Lett., 2008, 18, 668-693.For example, they can be synthesized according to the procedures in thescheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2014023083 or US2011/0217300. For example, they can be synthesizedaccording to the procedures in the scheme below.

Compounds with the moiety

can be synthesized can be synthesized based on the general proceduresdescribed in WO2008118468, WO2011075628, US2014/0336182, WO2008150827,and Lanman et al., Bioorg. Med. Chem. Lett., 24(24):5630-5634 (2014).For example, they can be synthesized according to the procedures in theschemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2013052699, WO2008118468, or Cushing et al., J. Med. Chem., 2015, 58,480-511. For example, they can be synthesized according to theprocedures in the schemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2012033144 or Han et al., ACS Med. Chem. Lett. 6:434-438 (2015). Forexample, they can be synthesized according to the procedures in theschemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2014060431, WO2014060432, WO2012146666, WO2014015675, or Ohta et al.,J. Org. Chem., 2009, 74, 8143. For example, they can be synthesizedaccording to the procedures in the schemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2008064018, WO2009064802, or Bowers et al., Bioorg. Med. Chem. Lett.,2011, 21, 1838-1843. For example, they can be synthesized according tothe procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2011008487 or WO2012125629. For example, they can be synthesizedaccording to the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2009064802, WO2011024871, WO2004064836, Tong et al., Bioorg. Med.Chem. Lett., 2008, 18, 5206-5208, or Schlewer et al., Acta ChemicaScandinavica, Series B: Organic Chemistry and Biochemistry, B38(10),815-19 (1984). For example, they can be synthesized according to theprocedures in the schemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2014015675 or WO2014015830. For example, they can be synthesizedaccording to the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2012003262, WO20070259851, WO2013146969, WO2010151740, or Cushing etal., J. Med. Chem., 2015, 58, 480-511. For example, they can besynthesized according to the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2011123751, WO2011075643, WO2008037783, US20110312979, US20120202785,or Li et al., Bioorg. Med. Chem. Lett., 2008, 18, 688-693. For example,they can be synthesized according to the procedures in the schemesbelow.

Compounds with the moiety

can be synthesized based on the general procedures described inUS20110313979 or Jablonowski et al., J. Med. Chem., 2003, 46, 3957-3960.For example, they can be synthesized according to the procedures in theschemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2008011560 or WO2011123751. For example, they can be synthesizedaccording to the procedures in the schemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2004069829, WO2011123751, US20120202785, or Bachelet et al., Eur. J.Med. Chem., 1985, 20, 425-427. For example, they can be synthesizedaccording to the procedures in the schemes below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2011075643. For example, they can be synthesized according to theprocedures in the schemes below.

(v) General Methods for Alkyne Synthesis:

A sealed vessled is charged with PdCl₂(MeCN)₂ and X-Phos (3:1 ratio ofX-Phos to PdCl₂(MeCN)₂, 5-15 mol % catalyst), cesium carbonate (1.5-3.0equiv) and propionitrile (0.5 M). The mixture is stirred for 5 min afterwhich the aryl bromide or aryl iodid substrate was added. After another5 minutes of stirring TMS-acetylene (3.0 equiv) is added and the flaskis sealed and heated at RT for 10 min follwed by 1 h of heating at 95°C. The reaction is allowed to cool after which it is concentrateddirectly onto silica gel and purified using flash silica gelchromatography (gradient of ethyl acetate/hexanes) to provide alkyneI-1.

Alkyne I-1 (1.0 equiv) is then dissolved in tetrahydrofuran (0.13 M) andcharged with TBAF (1.1 equiv, 1.0 M in tetrahydrofuran). The resultingmixture is stirred at RT for 6 h after which it is poured into saturatedbicarbonate solution and extracted with ethyl acetate. The organic layeris washed with brine and concentrated onto silica gel where it ispurified directly by flash silica gel chromatography (gradient of ethylacetate/hexanes) to provide aryl alkyne 1-2.

Aldehyde (1.0 equiv) is a dissolved in anhydrous methanol (0.2-0.5 mM)and charged with cesium carbonate (1.0 equiv) and cooled to 0-5° C.Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 equiv) is added dropwiseafter which the reaction is allowed to stir for 1-18 h after which thecrude mixture is concentrated onto silica gel and purified directly byflash silica gel chromatography to provide the desired alkyne J-1.

A secondary amine (1.0 equiv) is dissolved in acetonitrile (0.42 M) andpotassium carbonate (1.1 equiv) is added. The white suspension isstirred at 0-5° C. for 5 min after which point propargyl bromide (1.01equiv) is added dropwise over 3 min. The reaction is then stirred for anadditional 15 min at 0-5° C. and then at room temperature for 15 h. Theheterogeneous mixture is then filtered. The filtrate is concentratedunder reduced pressure, diluted with MTBE and washed with water (2×),brine (1×), dried over sodium sulfate and then filtered through celite.The resulting filtrate is concentrated and purified using flash silicagel chromatography to provide the desired alkyne K-1.

(v) General Methods for W_(d) Synthesis:

Compounds with the moiety

can be synthesized based on the general procedures described in Vega etal., Tetrahedron 1999, 55, 2317. For example, they can be synthesizedaccording to the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described in Garzónand Davies, Org. Lett., 2014, 16, 4850. For example, they can besynthesized according to the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described in Garzónand Davies, Org. Lett., 2014, 16, 4850. For example, they can besynthesized according to the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inCarballares et al., Tetrahedron Letters, 2007, 48(11), 2041-2045. Forexample, they can be synthesized according to the procedures in thescheme below.

Compounds with the moiety

can be synthesized based on the general procedures described inWO2015/086503. For example, they can be synthesized according to theprocedures in the scheme below strafing with compounds described inWO2015/086503.

Compounds with the moiety

can be synthesized based on the general procedures described in Williamset al., J. Am. Chem. Soc., 2014, 136, 8829-8836; and Castro et al., US2013/0267521. For example, they can be synthesized according to theprocedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described in Boyle etal., US 2008/0267942; Clark et al., WO 2009/038157; Bock et al., WO2013/128421; Petersen et al., Synthesis, 2014, 46, 1469-1474; and Castroet al., US 2013/0267521. For example, they can be synthesized accordingto the procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described in Petersenet al., Synthesis, 2014, 46, 1469-1474; Castro et al., US 2013/0267521.For example, they can be synthesized according to the procedures in thescheme below.

Compounds with the moiety

can be synthesized based on the general procedures described in Li etal., WO 2015/027124. For example, they can be synthesized according tothe procedures in the scheme below.

Compounds with the moiety

can be synthesized based on the general procedures described in Li etal., WO 2015/027124. For example, they can be synthesized according tothe procedures in the scheme below.

Example 1 Preparation of Compound 31

Step 1:

2-Aminopyrazolo[1,5-a]pyridine-3-carboxylic acid.2-Aminopyrazolo-[1,5-a]pyridine-3-carbonitrile (prepared according to WO2006/086539, 4.5 mmol) was dissolved in 15 mL methanol. HCl (12M, 6 mL)was added and the reaction was refluxed for 5 days after which it wasconcentrated onto silica gel and purified using flash silica gelchromatography (gradient of 0-10% MeOH/methylene chloride). Thismaterial was further purified using reverse phase HPLC (Interchim,gradient of 5-90% acetonitrile/water with 0.1% ammonium carbonate) toprovide methyl 2-aminopyrazolo[1,5-a]pyridine-3-carboxylate in 14%yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (ddd, J=6.7, 1.1, 1.1 Hz, 1H),7.71 (ddd, J=8.7, 1.2, 1.2 Hz, 1H), 7.42 (ddd, J=8.6, 7.0, 1.2 Hz, 1H),6.91 (ddd, J=6.9, 6.9, 1.5 Hz, 1H), 6.12 (s, 2H), 3.79 (s, 3H). ESI-MSm/z=192.1 [M+H]⁺. Methyl 2-aminopyrazolo[1,5-a]pyridine-3-carboxylate(0.063 mmol) was dissolved in 3 mL methanol. Sodium hydroxide (2M, 2.6equiv) was added and the reaction was heated for 4 h at 55° C. afterwhich an additional 80 μL of 2M NaOH was added followed by an additional12 h of heating at 55° C. A third portion of 2M NaOH (160 μL) was addedand the reaction was heated for an additional 9 h after which thereaction was allowed to cool. A solution of HCl (2M, 400 μL) was thenadded, the organic solvent was evaporated under a stream of air, and theresulting solid was collected via vacuum filtration to provide2-aminopyrazolo[1,5-a]pyridine-3-carboxylic acid used directly in thenext coupling. ESI-MS m/z=178.1 [M+H]⁺.

Step 2:

A suspension of 2-aminopyrazolo[1,5-a]pyridine-3-carboxylic acid (0.062mmol, 1.0 equiv) in N,N-dimethylforamide (2 mL),(S)-3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (0.065 mmol,1.1 equiv, prepared according to US 2013/267521), 1-hydroxybenzotriazolehydrate (0.075 mmol, 1.2 equiv), EDC HCl (0.075 mmol, 1.2 equiv) anddiisopropylethylamine (60 μL, 5.6 equiv) was allowed to stir at 23° C.for 24 h after which it is heated to 45° C. for an additional 3.5 h. Themixture was then added to 75 mL of water and stirred for 10 min afterwhich the resulting solid was collected by vacuum filtration. The crudesolid is then purified by reverse phase HPLC (Interchim, 10% ofacetonitrile/water with 0.1% ammonium carbonate) to provide compound 31in 29% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (ddd, J=6.8, 1.0, 1.0 Hz,1H), 7.76 (ddd, J=8.9, 1.2, 1.2 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H),7.63-7.44 (m, 7H), 7.42 (ddd, J=7.5, 1.7, 1.7 Hz, 1H), 7.35 (ddd, J=8.9,7.0, 1.2 Hz, 1H), 6.84 (s, 1H), 6.82 (ddd, J=8.4, 7.0, 1.2 Hz, 1H), 5.96(s, 2H), 4.48 (quin, J=6.7 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). ESI-MSm/z=457.9 [M+H]⁺. HPLC Purity: 99% AUC.

Example 2 Preparation of Compound 1

(S)-3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (20 mmol,1.0 equiv, prepared according to US 2013/267521),dichlorobis(acetonitrile) palladium (5 mol %), X-Phos (15 mol %), andcesium carbonate (24 mmol, 1.2 equiv) are suspended in 110 mLacetonitrile (degassed with argon). The entire mixture then degassedwith argon for 5 min. 4-Ethynyl-1-methyl-1H-pyrazole (22 mmol, 1.1equiv) was dissolved with 5 mL acetonitrile and added to the reactionmixture. The mixture is degassed for 2 min after which the yellowmixture was heated to 65-70° C. for 2 h after which an additionalportion of 4-ethynyl-1-methyl-1H-pyrazole (2.0 mmol, 0.1 equiv) in 1 mLacetonitrile was added and the mixture was reheated to 65-70° C. for 1 hafter which there was no SM by LC/MS ananlysis. The reaction mixture isallowed to cool after which it was filtered through a pad of celite,washed with extra acetonitrile (3×30 mL) and concentrated. The resultingmixture was treated with silica gel (12 g), concentrated under reducedpressure and purified using flash silica gel chromatography (gradient of0-5% methanol/methylene chloride) to provide intermediate 1-1 in 96%yield. ESI-MS m/z=369.3[M+H]⁺. Intermediate 1-1 was then converted tocompound 1 using the analogous coupling conditions as described forcompound 31 in Example 1. ESI-MS m/z=528.3[M+H]⁺.

Example 3 Preparation of Compound 3626

Step 1:

3-Amino-4-bromoisoquinoline. 3-Aminoisoquinoline (15 mmol, 1.0 equiv)was suspended in methanol (20 mL). A solution of N-bromosuccinimide (17mmol, 1.2 equiv) in methanol (75 mL) was added dropwise through anadditional funnel while keeping the internal temperature<25° C. Afterstirring at 23° C. for 1 h, the methanol is removed under vacuum and theresidue was partitioned between ethyl acetate and water. The layers wereseparated and the aqueous phase was back extracted with ethyl acetate(2×). The combined organic layers were dried with Na₂SO₄ andconcentrated onto silica gel (5 g) and purified using flash silica gelchromatography (gradient of 0-50% ethyl acetate/hexanes) to provide thedesired compound in 67% yield. 1H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H),7.96-7.82 (m, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.66 (ddd, J=8.5, 6.9, 1.5Hz, 1H), 7.41-7.29 (m, 1H), 5.07 (s, 2H). ESI-MS m/z=223.1 [M+H]⁺.

Step 2:

3-Aminoisoquinoline-4-carboxylic acid. 3-Amino-4-bromoisoquinoline (2.2mmol, 1.0 equiv) and Pd(dppf)Cl2-CH2Cl2 (1:1) (22 mol %) were suspendedin N,N-dimethylforamide (20 mL). Ethanol (30 equiv) and triethylamine (3equiv) were added and the flask was fitted with a balloon of carbonmonoxide. The mixture was evacuated and back-filled with CO five timesafter which it was heated to 80° C. for 16 h. The reaction was allowedto cool and partitioned between brine and ethyl acetate. The layers wereseparated and the aqueous later was back extracted with ethyl acetate(2×). The combined organic layers were dried with Na₂SO₄ andconcentrated onto silica gel (5 g) and purified using flash silica gelchromatography (gradient of 0-50% ethyl acetate/hexanes) to provide thedesired compound as a mixture of ˜1:1 3-aminoisoquinoline-4-carboxylicacid ethyl ester/starting material which is used directly in the nextstep. 3-Aminoisoquinoline-4-carboxylic acid ethyl ester mixture (1.0mmol ester, 1.0 equiv) was dissolved in methanol (15 mL). Lithiumhydroxide hydrate (10 mmol, 10 equiv) is added and the mixtures isheated to 60° C. for 4 h. The reaction is allowed to cool after whichthe solvent is removed under vacuum. The residue is suspended in waterand extracted with diethyl ether (2×). The water layer is acidified topH 5-6 with 20% citric acid, cooled to 0-5° C. and allowed to stir for15 min after which the resultant solid is isolated via vacuum filtrationand dried under vacuum to provide 3-aminoisoquinoline-4-carboxylic acidin 72% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.60 (d, J=8.8Hz, 1H), 7.92-7.81 (m, 1H), 7.62 (ddd, J=8.6, 6.9, 1.5 Hz, 1H), 7.26 (t,J=7.4 Hz, 1H). (CO₂H and NH₂ not visible). ESI-MS m/z=171.1 [M+H−H₂O]⁺.

Step 3:

(S)-3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (0.065 mmol,1.1 equiv, prepared according to US 2013/267521) (0.18 mmol, 1.0 equiv),3-aminoisoquinoline-4-carboxylic acid (0.20 mmol, 1.1 equiv),1-hydroxybenzotriazole hydrate (0.20 mmol, 1.1 equiv) and EDChydrochloride (0.20 mmol, 1.1 equiv) are dissolved inN,N-dimethylforamide (2 mL). Diisopropylethyl amine (0.36 mmol, 2.0equiv) was added and the reaction was allowed to stir for 6 h afterwhich it was partitioned between brine and ethyl acetate. The organiclayer was washed with brine (1×), dried over Na₂SO₄ and concentrated.The residue is suspended in acetonitrile, sonicated for 5 min and thenisolated via vacuum filtration to provide compound 3626 in 40% yield. 1HNMR (400 MHz, DMSO-d6) δ 9.09 (d, J=7.0 Hz, 1H), 8.89 (s, 1H), 7.91-7.83(m, 1H), 7.69-7.57 (m, 3H), 7.57-7.43 (m, 7H), 7.26-7.17 (m, 1H), 6.77(s, 1H), 5.89 (s, 2H), 4.62 (quin, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz,3H). ESI-MS m/z=469.3 [M+H]⁺. HPLC Purity>99% AUC.

Biological Activity Assessment

TABLE 5 In Vitro IC₅₀ data for selected compounds. RAJI Raw264.7 PI3K δ/RAJI δ/ p110 δ p110 γ PI3K γ Raw264.7 γ Compound PI3K α PI3K β PI3K δPI3K γ assay assay IC₅₀ IC₅₀ no. IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀(selectivity) (selectivity) 1 E2 B3 Y 31 C2 B3 W 3626 E2 E3The data in Table 5 are coded as follows.

For PI3K α, β, and δ IC₅₀: For PI3K γ IC₅₀: RAJI p110 δ assay IC₅₀Raw264.7 p110 γ assay IC₅₀ A2 = 1 to <500 nM A3 = 1 to <100 nM A4 = 1 to<100 nM A5 = 1 to <50 nM B2 = 500 to <1000 nM B3 = 100 to <500 nM B4 =100 to <500 nM B5 = 50 to <100 nM C2 = 1000 to <5000 nM C3 = 500 to<1000 nM C4 = 500 to <1000 nM C5 = 100 to <10000 nM D2 = 5000 to 10000nM D3 = 1000 to 5000 nM D4 = 1000 to 10000 nM E2 = >10000 nM E3 = >5000nM δ/γ IC₅₀ selectivity: V = 0.1 to 1 W = >1 to <10 X = 10 to <50 Y = 50to <850 ND = not determined

Example 4 PI3-Kinase HTRF™ Assay

A PI3-Kinase HTRF® assay kit (cat No. 33-016) purchased from MilliporeCorporation is used to screen compounds provided herein. This assay usesspecific, high affinity binding of the GRP1 pleckstrin homology (PH)domain to PIP3, the product of a Class 1A or 1B PI3 Kinase acting on itsphysiological substrate PIP2. During the detection phase of the assay, acomplex is generated between the GST-tagged PH domain and biotinylatedshort chain PIP3. The biotinylated PIP3 and the GST-tagged PH domainrecruited fluorophores (Streptavidin-Allophycocyanin andEuropium-labeled anti-GST respectively) to form the fluorescenceresonance energy transfer (FRET) architecture, generating a stabletime-resolved FRET signal. The FRET complex is disrupted in acompetitive manner by non-biotinylated PIP3, a product formed in the PI3Kinase assay.

PI3 Kinase α, γ or δ activity is assayed using the PI3 Kinase HTRF®assay kit (catalogue No. 33-016) purchased from Millipore Corporation.Purified recombinant PI3Kα (catalogue No. 14-602-K), PI3Kβ (catalogueNo. 14-603-K), PI3Kγ (catalogue No. 14-558-K), and PI3Kδ (catalogue No.14-604-K) are obtained from Millipore Corporation. Purified recombinantPI3K enzyme is used to catalyze the phosphorylation ofphosphatidylinositol 4,5-bisphosphate (PIP2 at 10 μM) tophosphatidylinositol 3,4,5-trisphosphate (PIP3) in the presence of 10 μMATP. The assay is carried out in 384-well format and detected using aPerkin Elmer EnVision Xcite Multilabel Reader. Emission ratios areconverted into percent inhibitions and imported into GraphPad Prismsoftware. The concentration necessary to achieve inhibition of enzymeactivity by 50% (IC₅₀) is calculated using concentrations ranging from20 μM to 0.1 nM (12-point curve). IC₅₀ values are determined using anonlinear regression model available in GraphPad Prism 5.

Example 5 Chemical Stability

The chemical stability of one or more subject compounds is determinedaccording to standard procedures known in the art. The following detailsan exemplary procedure for ascertaining chemical stability of a subjectcompound. The default buffer used for the chemical stability assay isphosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can beused. A subject compound is added from a 100 μM stock solution to analiquot of PBS (in duplicate) to give a final assay volume of 400 μL,containing 5 μM test compound and 1% DMSO (for half-life determination atotal sample volume of 700 μL is prepared). Reactions are incubated,with shaking, for 24 hours at 37° C.; for half-life determinationsamples are incubated for 0, 2, 4, 6, and 24 hours. Reactions arestopped by adding immediately 100 μL of the incubation mixture to 100 μLof acetonitrile and vortexing for 5 minutes. The samples are then storedat −20° C. until analysis by HPLC-MS/MS. Where desired, a controlcompound or a reference compound such as chlorambucil (5 μM) is testedsimultaneously with a subject compound of interest, as this compound islargely hydrolyzed over the course of 24 hours. Samples are analyzed via(RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLCconditions consist of a binary LC pump with autosampler, a mixed-mode,C12, 2×20 mm column, and a gradient program. Peak areas corresponding tothe analytes are recorded by HPLC-MS/MS. The ratio of the parentcompound remaining after 24 hours relative to the amount remaining attime zero, expressed as percent, is reported as chemical stability. Incase of half-life determination, the half-life is estimated from theslope of the initial linear range of the logarithmic curve of compoundremaining (%) vs. time, assuming first order kinetics.

Example 6 Expression and Inhibition Assays of p110α/p85α, p110β/p85α,p110δ/p85α, and p110γ

Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC₅₀ values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl₂), and freshly sonicated phosphatidylinositol (100 μg/ml).Reactions are initiated by the addition of ATP containing 10 μCi ofγ-32P-ATP to a final concentration of 10 or 100 μM and allowed toproceed for 5 minutes at room temperature. For TLC analysis, reactionsare then terminated by the addition of 105 μL 1N HCl followed by 160 μLCHCl₃:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged,and the organic phase is transferred to a new tube using a gel loadingpipette tip precoated with CHCl₃. This extract is spotted on TLC platesand developed for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC₅₀ determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including, but notlimited to, PI 3-Kinase α, β, δ, and γ. An exemplary system is PI3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried outaccording to the procedures suggested by the manufacturer. Briefly, theassay is a time resolved FRET assay that indirectly measures PIP3product formed by the activity of a PI3-K. The kinase reaction isperformed in a microtiter plate (e.g., a 384 well microtiter plate). Thetotal reaction volume is approximately 20 μL per well. In the firststep, each well receives 2 μL of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, approximately 14.5 μLof a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added perwell for a final concentration of 0.25-0.3 μg/mL kinase and 10 μM PIP2.The plate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 μL of ATP (diluted in 1× reaction buffer) isadded per well for a final concentration of 10 μM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 μL of Stop Solution per well and then 5 μL ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC₅₀s are generated using GraphPad Prism 5.

Example 7 B Cell Activation and Proliferation Assay

The ability of one or more subject compounds to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing Alamar Blue reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 μL at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 μ bME+5 mMHEPES). A compound provided herein is diluted in B Cell Media and addedin a 10 μL volume. Plates are incubated for 30 min at 37° C. and 5% CO₂(0.2% DMSO final concentration). A 50 μL B cell stimulation cocktail isthen added containing either 10 μg/mL LPS or 5 μg/mL F(ab′)2 Donkeyanti-mouse IgM plus 2 ng/mL recombinant mouse IL4 in B Cell Media.Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volume of 15μL of Alamar Blue reagent is added to each well and plates are incubatedfor 5 hours at 37° C. and 5% CO₂ Alamar Blue fluoresce is read at560Ex/590Em, and IC₅₀ or EC₅₀ values are calculated using GraphPad Prism5.

Example 8 Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation can be determined according to standard procedures knownin the art. For instance, an in vitro cellular proliferation assay canbe performed to measure the metabolic activity of live cells. The assayis performed in a 96-well microtiter plate using Alamar Blue reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 μL at 5,000 cells/well in Tumor Cell Media. A compoundprovided herein is diluted in Tumor Cell Media and added in a 10 μLvolume. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 10 μL of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37° C. and 5% CO₂ Alamar Blue fluoresce is readat 560Ex/590Em, and IC₅₀ values are calculated using GraphPad Prism 5.

Example 9 Antitumor Activity In Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-Refractory Tumor Models

1. Clinically-Derived Ovarian Carcinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient. The compounds describedherein are administered to nude mice bearing staged tumors using anevery 2 days×5 schedule.

2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein. The compoundsdescribed herein can be administered to mice bearing staged tumors on anevery 2 days×5 schedule.

3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel. Thecompounds described herein can be administered to mice bearing stagedtumors on an every 2 days×5 schedule.

4. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. The compounds described herein can be administeredto mice bearing staged tumors on an every 2 days×5 schedule. One or morecompounds as provided herein can be used in combination with othertherapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

In one aspect, compounds provided herein may be evaluated in thefollowing models according to methods known in the art. The dosage andschedule of administration may be varied depending on the model. Theresults may be evaluated with those of selective delta inhibitors, andcombinations of delta and gamma inhibitors, and/or with antibodies thatblock specific inhibitory receptors.

Pancreatic Models

KPC model is a transgenic mouse model of pancreatic ductaladenocarcinoma (PDA), in which there is conditional expression of bothmutant KrasG12D and p53R172H alleles in pancreatic cells. Tumors developspontaneously in this mouse over a period of 3-6 months, and can be usedto study prophylactic, as well as therapeutic efficacy with novelagents. Cells from these KPC tumors can also be adoptively transferredinto syngeneic B6.129 hybrid mice, creating a model with a shorterlatency period and allowing large number of animals with tumors to besynchronously established. See e.g., Cancer Cell 7:468 (2005).

Pan02 model: The murine pancreatic adenocarcinoma cell line Pan02 is anonmetastatic tumor line, syngeneic to C57BL/6. It can be studiedfollowing s.c. injection into flank, or orthotopically followinginjection directly into the pancreas. See e.g., Cancer Res. 44: 717-726(1984).

Lung Models

LLC Lewis Lung Adenocarcinoma model: LLC cells are derived from aspontaneous lung tumor from a C57BL/6 mouse and can be studied as a s.c.tumor when injected in the flank, or as an orthotopic tumor if injectedi.v., following which it localizes to the lung.

LLC cells have also been modified to express a peptide from ovalbumin(LL2-OVA cells). Use of these cells, following either s.c. or i.v.injection, allows the tracking of OVA-specific CD8+ lymphocytes andmeasurement of effects of therapy on the adaptive immune responseagainst the tumor. See e.g., Science 330:827 (2010).

Breast Model

The 4T1 mammary carcinoma is a transplantable tumor cell line that growsin syngeneic BALB/c mice. It is highly tumorigenic and invasive and,unlike most tumor models, can spontaneously metastasize from the primarytumor in the mammary gland to multiple distant sites including lymphnodes, blood, liver, lung, brain, and bone. See e.g., Current Protocolsin Immunology Unit 20.2 (2000).

Lymphoma Model

EL4 is a C57BL/6 T thymoma and EG7 is an OVA-expressing subclone of EL4.The parental EL4 line has been modified to constitutively expressluciferase, which allows non-invasive imaging of tumor growth throughoutthe animal using the Xenogen imaging platform.

Melanoma Model

B16 murine melanoma cells are syngeneic with C57BL/6 mice and can bestudied after s.c. or i.v. injection. Placement at either site willresult in metastases to lung and other organs. This model has beenextensively studied in terms of the role that inhibitory receptors playin the anti-tumor immune response. See e.g., PNAS 107:4275 (2010).

Example 10 Microsome Stability Assay

The stability of one or more subject compounds is determined accordingto standard procedures known in the art. For example, stability of oneor more subject compounds is established by an in vitro assay. Forexample, an in vitro microsome stability assay is established thatmeasures stability of one or more subject compounds when reacting withmouse, rat or human microsomes from liver. The microsome reaction withcompounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1μL of 10.0 mg/mL NADPH; 75 μL of 20.0 mg/mL mouse, rat or human livermicrosome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH₂O.Negative control (without NADPH) tube contains 75 μL of 20.0 mg/mLmouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer,and 525 μL of ddH₂O. The reaction is started by adding 1.0 μL of 10.0 mMtested compound. The reaction tubes are incubated at 37° C. 100 μLsample is collected into new Eppendorf tube containing 300 μL coldmethanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples arecentrifuged at 15,000 rpm to remove protein. Supernatant of centrifugedsample is transferred to new tube. Concentration of stable compoundafter reaction with microsome in the supernatant is measured by LiquidChromatography/Mass Spectrometry (LC-MS).

Example 11 Plasma Stability Assay

The stability of one or more subject compounds in plasma is determinedaccording to standard procedures known in the art. See, e.g., RapidCommun. Mass Spectrom., 10: 1019-1026. The following procedure is anHPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A subject compound is added from a 400 μM stocksolution to an aliquot of pre-warmed plasma to give a final assay volumeof 400 μL (or 800 μL for half-life determination), containing 5 μM testcompound and 0.5% DMSO. Reactions are incubated, with shaking, for 0minutes and 60 minutes at 37 C, or for 0, 15, 30, 45 and 60 minutes at37 C for half life determination. Reactions are stopped by transferring50 μL of the incubation mixture to 200 μL of ice-cold acetonitrile andmixed by shaking for 5 minutes. The samples are centrifuged at 6000×gfor 15 minutes at 4° C. and 120 μL of supernatant removed into cleantubes. The samples are then evaporated to dryness and submitted foranalysis by HPLC-MS/MS.

In one embodiment, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 12 Kinase Signaling in Blood

PI3K/Akt/mTOR signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. (2007) 434:131-54). This method is by nature asingle cell assay so that cellular heterogeneity can be detected ratherthan population averages. This allows concurrent distinction ofsignaling states in different populations defined by other markers.Phosflow is also highly quantitative To test the effects of one or morecompounds provided herein, unfractionated splenocytes, or peripheralblood mononuclear cells are stimulated with anti-CD3 to initiate T-cellreceptor signaling. The cells are then fixed and stained for surfacemarkers and intracellular phosphoproteins. Inhibitors provided hereininhibit anti-CD3 mediated phosphorylation of Akt -S473 and S6, whereasrapamycin inhibits S6 phosphorylation and enhances Akt phosphorylationunder the conditions tested.

Similarly, aliquots of whole blood are incubated for 15 minutes withvehicle (e.g., 0.1% DMSO) or kinase inhibitors at variousconcentrations, before addition of stimuli to crosslink the T cellreceptor (TCR) (anti-CD3 with secondary antibody) or the B cell receptor(BCR) using anti-kappa light chain antibody (Fab′2 fragments). Afterapproximately 5 and 15 minutes, samples are fixed (e.g., with cold 4%paraformaldehyde) and used for phosflow. Surface staining is used todistinguish T and B cells using antibodies directed to cell surfacemarkers that are known to the art. The level of phosphorylation ofkinase substrates such as Akt and S6 are then measured by incubating thefixed cells with labeled antibodies specific to the phosphorylatedisoforms of these proteins. The population of cells are then analyzed byflow cytometry.

Example 13 Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) patientsupon initial diagnosis or relapse. Live cells are isolated and enrichedfor CD19+ CD34+ B cell progenitors. After overnight liquid culture,cells are plated in methocult GF+ H4435 (Stem Cell Technologies),supplemented with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3ligand, and erythropoietin) and various concentrations of knownchemotherapeutic agents in combination with compounds of the presentdisclosure. Colonies are counted by microscopy 12-14 days later. Thismethod can be used to test for evidence of additive or synergisticactivity.

Example 14 In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g., Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells are administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days are euthanizedand lymphoid organs are harvested for analysis Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors are given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabeled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompounds provided herein in combination with known chemotherapeuticagents can reduce leukemic blood cell counts as compared to treatmentwith known chemotherapeutic agents (e.g., Gleevec) alone under theconditions tested.

Example 15 Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R2KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus patients show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R2KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Sle1z.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

The NZB/W F1 mice that spontaneously develop a systemic autoimmunedisease is a model of lupus. The murine NZB/W F1 lupus model has manyfeatures of human lupus, and is characterized by elevated levels ofanti-nuclear and anti-dsDNA autoantibodies; a critical role forplasmacytoid dendritic cells and IFN-α; T-cell, B-cell, macrophageinvolvement; pheymolytic anemia; progressive immune complexglomerulonephritis; proteinurea; severity and incidence more pronouncedin females; and decreased survival. Treatment with a compound providedherein can be determined by evaluation of urine protein scores, organweights, plasma anti-dsDNA IgG levels, and histopathology of thekidneys. The mice are treated starting at 20 weeks of age for aprofilactic model and at 23 weeks of age for a therapeutic model. Bloodand urine samples are obtained throughout the testing period, and testedfor antinuclear antibodies (in dilutions of serum) or proteinconcentration (in urine). Serum is also tested for anti-ssDNA andanti-dsDNA antibodies by ELISA. Glomerulonephritis is assessed in kidneysections stained with H&E at the end of the study, or survival can be anendpoint. For example, the proteozome inhibitor Bortezimib is effectiveat blocking disease in the NZB/W model in both the profilactic andtherapeutic model with reductions in auto-antibody production, kidneydamage, and improvements in survival (Nature Medicine 14,748-755(2008)).

Lupus disease model mice such as R2KO, BXSB or MLR/lpr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of: vehicle, RAD001 at about 10 mg/kg, or compounds providedherein at approximately 1 mg/kg to about 500 mg/kg. Blood and urinesamples are obtained throughout the testing period, and tested forantinuclear antibodies (in dilutions of serum) or protein concentration(in urine). Serum is also tested for anti-ssDNA and anti-dsDNAantibodies by ELISA Animals are euthanized at day 60 and tissuesharvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This established art model can be employed to demonstrate that thekinase inhibitors provided herein can suppress or delay the onset oflupus symptoms in lupus disease model mice.

Example 16 Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from a γ ray source. About1 hr after the radiation dose, mice are injected with about 1×106leukemic cells from early passage p190 transduced cultures (e.g., asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×10⁶ normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment, a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e g., imatinib at about 70 mg/kg twicedaily). For the first phase, p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect pAkt-S473 and pS6-S235/236 in hCD4-gated cells without prior sorting.These signaling studies are particularly useful if, for example,drug-treated mice have not developed clinical leukemia at the 35 daytime point. Kaplan-Meier plots of survival are generated and statisticalanalysis done according to methods known in the art. Results from p190cells are analyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μL) are obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein.

This general assay known in the art can be used to demonstrate thateffective therapeutic doses of the compounds provided herein can be usedfor inhibiting the proliferation of leukemic cells.

Example 17 Matrigel Plug Angiogenesis Assay

Matrigel containing test compounds are injected subcutaneously orintraocularly, where it solidifies to form a plug. The plug is recoveredafter 7-21 days in the animal and examined histologically to determinethe extent to which blood vessels have entered it. Angiogenesis ismeasured by quantification of the vessels in histologic sections.Alternatively, fluorescence measurement of plasma volume is performedusing fluorescein isothiocyanate (FITC)-labeled dextran 150. The resultsare expected to indicate one or more compounds provided herein thatinhibit angiogenesis and are thus expected to be useful in treatingocular disorders related to aberrant angiogenesis and/or vascularpermeability.

Example 18 Corneal Angiogenesis Assay

A pocket is made in the cornea, and a plug containing an angiogenesisinducing formulation (e.g., VEGF, FGF, or tumor cells), when introducedinto this pocket, elicits the ingrowth of new vessels from theperipheral limbal vasculature. Slow-release materials such as ELVAX(ethylene vinyl copolymer) or Hydron are used to introduce angiogenesisinducing substances into the corneal pocket. Alternatively, a spongematerial is used.

The effect of putative inhibitors on the locally induced (e.g., spongeimplant) angiogenic reaction in the cornea (e.g., by FGF, VEGF, or tumorcells). The test compound is administered orally, systemically, ordirectly to the eye. Systemic administration is by bolus injection or,more effectively, by use of a sustained-release method such asimplantation of osmotic pumps loaded with the test inhibitor.Administration to the eye is by any of the methods described hereinincluding, but not limited to eye drops, topical administration of acream, emulsion, or gel, intravitreal injection.

The vascular response is monitored by direct observation throughout thecourse of the experiment using a stereomicroscope in mice. Definitivevisualization of the corneal vasculature is achieved by administrationof fluorochrome-labeled high-molecular weight dextran. Quantification isperformed by measuring the area of vessel penetration, the progress ofvessels toward the angiogenic stimulus over time, or in the case offluorescence, histogram analysis or pixel counts above a specific(background) threshold.

The results can indicate one or more compounds provided herein inhibitangiogenesis and thus can be useful in treating ocular disorders relatedto aberrant angiogenesis and/or vascular permeability.

Example 19 Microtiter-Plate Angiogenesis Assay

The assay plate is prepared by placing a collagen plug in the bottom ofeach well with 5-10 cell spheroids per collagen plug each spheroidcontaining 400-500 cells. Each collagen plug is covered with 1100 μL ofstorage medium per well and stored for future use (1-3 days at 37° C.,5% CO₂). The plate is sealed with sealing. Test compounds are dissolvedin 200 μL assay medium with at least one well including a VEGF positivecontrol and at least one well without VEGF or test compound as anegative control. The assay plate is removed from the incubator andstorage medium is carefully pipeted away. Assay medium containing thetest compounds are pipeted onto the collagen plug. The plug is placed ina humidified incubator for (37° C., 5% CO₂) 24-48 hours. Angiogenesis isquantified by counting the number of sprouts, measuring average sproutlength, or determining cumulative sprout length. The assay can bepreserved for later analysis by removing the assay medium, adding 1 mLof 10% paraformaldehyde in Hanks BSS per well, and storing at 4° C. Theresults are expected to identify compounds that inhibit angiogenesis invarious cell types tested, including cells of ocular origin.

Example 20 Combination Use of PI3K-δ Inhibitors and Agents that InhibitIgE Production or Activity

The compounds as provided herein can present synergistic or additiveefficacy when administered in combination with agents that inhibit IgEproduction or activity. Agents that inhibit IgE production include, forexample, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as Omalizumab and TNX-901.

One or more of the subject compounds capable of inhibiting PI3K-δ can beefficacious in treatment of autoimmune and inflammatory disorders(AIID), for example, rheumatoid arthritis. If any of the compoundscauses an undesired level of IgE production, one can choose toadminister it in combination with an agent that inhibits IgE productionor IgE activity. Additionally, the administration of PI3K-δ or PI3K-δ/γinhibitors as provided herein in combination with inhibitors of mTOR canalso exhibit synergy through enhanced inhibition of the PI3K pathway.Various in vivo and in vitro models can be used to establish the effectof such combination treatment on AIID including, but not limited to: (a)in vitro B-cell antibody production assay, (b) in vivo TNP assay, and(c) rodent collagen induced arthritis model.

(a) B-Cell Assay

Mice are euthanized, and the spleens are removed and dispersed through anylon mesh to generate a single-cell suspension. The splenocytes arewashed (following removal of erythrocytes by osmotic shock) andincubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads(Miltenyi Biotec). The bead-bound cells are separated from unbound cellsusing a magnetic cell sorter. The magnetized column retains the unwantedcells and the resting B cells are collected in the flow-through.Purified B-cells are stimulated with lipopolysaccharide or an anti-CD40antibody and interleukin 4. Stimulated B-cells are treated with vehiclealone or with PI3K-δ inhibitors as provided herein with and without mTORinhibitors such as rapamycin, rapalogs, or mTORC1/C2 inhibitors. Theresults are expected to show that in the presence of mTOR inhibitors(e.g., rapamycin) alone, there is little to no substantial effect on IgGand IgE response. However, in the presence of PI3K-δ and mTORinhibitors, the B-cells are expected to exhibit a decreased IgG responseas compared to the B-cells treated with vehicle alone, and the B-cellsare expected to exhibit a decreased IgE response as compared to theresponse from B-cells treated with PI3K-δ inhibitors alone.

(b) TNP Assay

Mice are immunized with TNP-Ficoll or TNP-KHL and treated with: vehicle,a PI3K-δ inhibitor, an mTOR inhibitor, for example rapamycin, or aPI3K-δ inhibitor in combination with an mTOR inhibitor such asrapamycin. Antigen-specific serum IgE is measured by ELISA using TNP-BSAcoated plates and isotype specific labeled antibodies. It is expectedthat mice treated with an mTOR inhibitor alone exhibit little or nosubstantial effect on antigen specific IgG3 response and nostatistically significant elevation in IgE response as compared to thevehicle control. It is also expected that mice treated with both PI3K-δinhibitor and mTOR inhibitor exhibit a reduction in antigen specificIgG3 response as compared to the mice treated with vehicle alone.Additionally, the mice treated with both PI3K-δ inhibitor and mTORinhibitor exhibit a decrease in IgE response as compared to the micetreated with PI3K-δ inhibitor alone.

(c) Rat Collagen Induced Arthritis Model

Female Lewis rats are anesthetized and given collagen injectionsprepared and administered as described previously on day 0. On day 6,animals are anesthetized and given a second collagen injection. Calipermeasurements of normal (pre-disease) right and left ankle joints areperformed on day 9. On days 10-11, arthritis typically occurs and ratsare randomized into treatment groups. Randomization is performed afterankle joint swelling is obviously established and there is good evidenceof bilateral disease.

After an animal is selected for enrollment in the study, treatment isinitiated Animals are given vehicle, PI3K-δ inhibitor, or PI3K-δinhibitor in combination with rapamycin. Dosing is administered on days1-6. Rats are weighed on days 1-7 following establishment of arthritisand caliper measurements of ankles taken every day. Final body weightsare taken on day 7 and animals are euthanized

The combination treatment using a compound as provided herein andrapamycin can provide greater efficacy than treatment with PI3K-δinhibitor alone.

Example 21 Delayed Type Hypersensitivity Model

DTH is induced by sensitizing 60 BALB/c male mice on day 0 and day 1with a solution of 0.05% 2,4 dinitrofluorobenzene (DNFB) in a 4:1acetone/olive oil mixture. Mice are gently restrained while 20 μL ofsolution is applied to the hind foot pads of each mouse. The hind footpads of the mice are used as they represent an anatomical site that canbe easily isolated and immobilized without anesthesia. On day 5, miceare administered a single dose of vehicle, a compound provided herein at10, 3, 1, or 0.3 mg/kg, or dexamethasone at a dose of 5 mg/kg by oralgavage. Thirty minutes later mice are anaesthetized, and a solution of0.25% DNFB in a 4:1 acetone/olive oil solution is applied to the leftinner and outer ear surface. This application results in the inductionof swelling to the left ear and under these conditions, all animalsresponded to this treatment with ear swelling. A vehicle controlsolution of 4:1 acetone/olive oil is applied to the right inner andouter ear. Twenty four hours later, mice are anaesthetized, andmeasurements of the left and right ear are taken using a digitalmicrometer. The difference between the two ears is recorded as theamount of swelling induced by the challenge of DNFB. Drug treatmentgroups are compared to vehicle control to generate the percent reductionin ear swelling. Dexamethasone is routinely used as a positive controlas it has broad anti-inflammatory activity.

Example 22 Peptidoglycan-Polysaccharide Rat Arthritic Model

(a) Systemic Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflumne in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intraperitoneally (i.p.)with a single injection of purified PG-PS 10S Group A, D58 strain(concentration 25 μg/g of bodyweight) suspended in sterile 0.85% saline.Each animal receives a total volume of 500 microliters administered inthe lower left quadrant of the abdomen using a 1 milliliter syringe witha 23 gauge needle. Placement of the needle is critical to avoidinjecting the PG-PS 10S into either the stomach or caecum. Animals areunder continuous observation until fully recovered from anesthesia andmoving about the cage. An acute response of a sharp increase in anklemeasurement, typically 20% above baseline measurement can peak in 3-5days post injection. Treatment with test compounds can be PO, SC, IV orIP. Rats are dosed no more than two times in a 24 hour time span.Treatment can begin on day 0 or any day after that through day 30. Theanimals are weighed on days 0, 1, 2, 3, 4, 5, 6, 7 and beginning againon day 12-30 or until the study is terminated. Paw/ankle diameter ismeasured with a digital caliper on the left and right side on day 0prior to injection and again on day 1, 2, 3, 4, 5, 6 and 7. On day 12,measurements begin again and continue on through day 30. At this time,animals can be anesthetized with isoflurane, as described above, andterminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are then euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

(b) Monoarticular Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflumne in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intra-articular (i.a.)with a single injection of purified PG-PS 100P Group A, D58 strain(concentration 500 μg/mL) suspended in sterile 0.85% saline. Each ratreceives a total volume of 10 microliters administered into thetibiotalar joint space using a 1 milliliter syringe with a 27 gaugeneedle Animals are under continuous observation until fully recoveredfrom anesthesia and moving about the cage Animals that respond 2-3 dayslater with a sharp increase in ankle measurement, typically 20% abovebaseline measurement on the initial i.a. injection, are included in thestudy. On day 14, all responders are anesthetized again using theprocedure previously described. Animals receive an intravenous (I.V.)injection of PG-PS (concentration 250 μL/mL). Each rat receives a totalvolume of 400 microliters administered slowly into the lateral tail veinusing a 1 milliliter syringe with a 27 gauge needle. Baseline anklemeasurements are measured prior to IV injection and continue through thecourse of inflammation or out to day 10. Treatment with test compoundswill be PO, SC, IV or IP. Rats are dosed no more than two times in a 24hour time span. Treatment can begin on day 0 or any day after thatthrough day 24. The animals are weighed on days 0, 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. Paw/anklediameter is measured with a digital caliper on the left and right sideon day 0 prior to injection and again on day 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. At thistime, animals can be anesthetized with isoflurane, as described above,and terminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

Example 23 Mice Models for Asthma

Efficacy of a compound provided herein in treating, preventing and/ormanaging asthma can be assessed using an conventional animal modelsincluding various mice models described in, for example, Nials et al.,Dis Model Mech. 1(4-5): 213-220 (2008).

(a) Acute Allergen Challenge Models

Several models are known in the art and any of such models can be used.Although various allergens can be used to induce asthma-like conditions,the principle is consistent throughout the methods. Briefly, asthma-likeconditions are induced through multiple systemic administration of theallergen (e.g., ova, house dust mite extracts and cockroach extracts) inthe presence of an adjuvant such as aluminum hydroxide. Alternatively,an adjuvant-free system can be used, but it usually requires a highernumber of exposures to achieve suitable sensitization. Once induced,animals exhibit many key features of clinical asthma such as: elevatedlevels of IgE; airway inflammation; goblet cell hyperplasia; epithelialhypertrophy; AHR ro specific stimuli; and early and late phasebronchoconstriction. Potential efficacy of a compound thus can beassessed by determining whether one or more of these clinical featuresare reversed or mitigated.

(b) Chronic Allergen Challenge Models

Chronic allergen challenge models aim to reproduce more of the featuresof the clinical asthma, such as airway remodeling and persistent AHR,than acute challenge models. While allergens similar to those used inacute allergen challenge models can be used, in chronic allergenchallenge models, animals are subjected to repeated exposure of theairways to low levels of allergen for a period of up to 12 weeks. Onceinduced, animals exhibit key features of human asthma such as:allergen-dependent sensitization; a Th2-dependent allergic inflammationcharacterized by eosinophillic influx into the airway mucosa; AHR; andairway remodeling as evidenced by goblet cell hyperplasia, epithelialhypertrophy, subepithelial or peribronchiolar fibrosis. Potentialefficacy of a compound thus can be assessed by determining whether oneor more of these clinical features are reversed or mitigated.

Example 24 Models for Psoriasis

Efficacy of a compound provided herein in treating, preventing and/ormanaging psoriasis can be assessed using an conventional animal modelsincluding various animal models described in, for example, Boehncke etal., Clinics in Dermatology, 25: 596-605 (2007).

As an example, the mouse model based on adoptive transfer ofCD4⁺CD45RB^(hi) T cells described in Hong et al., J. Immunol., 162:7480-7491 (1999) can be made. Briefly, female BALB/cBY (donor) andC.B.-17/Prkdc scid/scid (recipient) mice are housed in a specificpathogen-free environment and are used between 6 and 8 weeks of age.CD4⁺ T cells are enriched from BALB/cBy splenocytes using a mouse CD4enrichment kit. The cells are then labeled with PE-conjugated anti-CD4,FITC-conjugated anti-CD45RB, and APC-conjugated anti-CD25 antibodies.Cells are sorted using a cell sorter. CD4⁺CD45RB^(hi)CD25 cells arecollected. Cells are resuspended in saline and 4×10⁸ cells/mouse areinjected i.p. into C.B.-17/Prkdc scid/scid mice. Mice may be dosed withLPS, cytokines, or antibodies as necessary. Mice are monitored forexternal signs of skin lesions twice each week. After the termination,ear, back skin, lymph nodes and spleen may be collected for further exvivo studies.

Example 25 Models for Scleroderma

A compound's efficacy in treating scleroderma can be tested using animalmodels. An exemplary animal model is a mouse model for sclerodermainduced by repeated local injections of bleomycin (“BLM”) described, forexample, in Yamamoto et al., J Invest Dermatol 112: 456-462 (1999), theentirety of which is incorporated herein by reference. This mouse modelprovides dermal sclerosis that closely resembles systemic sclerosis bothhistologically and biochemically. The sclerotic changes observed in themodel include, but are not limited to: thickened and homogenous collagenbundles and cellular filtrates; gradual increase in number of mastcells; degranulation of mast cells; elevated histamine release; increasein hydroxyproline in skin; presence of anti-nuclear antibody in serum;and strong expression of transforming growth factor β-2 mRNA. Therefore,efficacy of a compound in treating scleroderma can be assessed bymonitoring the lessening of one or more of these changes.

Briefly, the following exemplary procedures can be used to generate themouse model for scleroderma: Specific pathogen-free, female BALB/C miceand C3H mice of 6 weeks old, weighing about 20 g, are purchased andmaintained with food and water ad libitum. BLM is dissolved in PBS atdiffering concentrations and sterilized with filtration. Aliquots ofeach concentration of BLM or PBS are injected subcutaneously into theshaved back of the mice daily for 1-4 weeks with a needle.Alternatively, mice are injected every other day.

Histolopathological and biochemical changes induced can be assessedusing any methods commonly practiced in the field. For example,histopathological changes can be assessed using a standardavidine-biotin peroxidase technique with anti-L3T4 monoclonal antibody,anti-Lyt2 monoclonal antibody, anti-mouse pan-tissue-fixed macrophageantibody, anti-stem cell factor monoclonal antibody, anti-transforminggrowth factor-β polyclonal antibody, and anti-decorin antibody. Cytokineexpression of cellular infiltrates can be assessed by using severalanti-cytokine antibodies. Hydroxyproline level can be assessed byhydrolyzing skin pieces with hydrochloric acid, neutralizing with sodiumhydroxide, and colorimetrically assessing the hydrolates at 560 nm withp-dimethylaminobenzaldehyde. Pepsin-resistant collagen can be assessedby treating collagen sample extracted from biopsied tissues andanalyzing by polyacrylamide stacking gel electrophoresis. Mast cells canbe identified by toluidine blue, and cells containing matachromaticgranules can be counted under high magnification of a light microscope.Serum levels of various cytokines can be assessed by enzyme-linkedimmunosorbent assay, and mRNA levels of the cytokines can be assessed byreverse-transcriptase polymerase chain reaction. Autoantibodies in serumcan be detected using 3T3 fibroblasts as the substrate for thescreening.

Example 26 Models for Myositis

A compound's efficacy in treating myositis (e.g., dermatomyositis) canbe tested using animal models known in the art. One such example is thefamilial canine dermatomyositis model described in Hargis et al., AJP120(2): 323-325 (1985). Another example is the rabbit myosin inducedmouse model described in Phyanagi et al., Arthritis & Rheumatism,60(10): 3118-3127 (2009).

Briefly, 5-week old male SJL/J mice are used. Purified myosin fromrabbit skeletal muscle (6.6 mg/ml) is emulsified with an equal amount ofFreund's complete adjuvant and 3.3 mg/ml Mycobacterium butyricum. Themice are immunized repeatedly with emulsified rabbit myosin. Oncemyositis is induced, inflammatory cell filtration and necrotic musclefiber should be evident in the model. In the muscles of animals, CD4⁺ Tcells are mainly located in the perimysum and CD8⁺ T cells are mainlylocated in the endomysium and surround non-necrotic muscle fibers. TNFα,IFNγ and perform are up-regulated and intercellular adhesion molecule 1is increased in the muscles.

To assess the efficacy of a compound, following administration of thecompound through adequate route at specified dose, the mice are killedand muscle tissues are harvested. The muscle tissue is immediatelyfrozen in chilled isopentane precooled in liquid nitrogen, and thencryostat sections are prepared. The sections are stained withhematoxylin and eosin for counting of number of infiltrated cells. Threesections from each mouse are prepared and photomicrographs are obtained.For immunohistochemical tests, cryostat sections of muscle are dried andfixed in cold acetone at −20° C. The slides are rehydrated in PBS, andthen endogeneous peroxide activity is blocked by incubation in 1%hydrogen peroxide. The sections are incubated overnight with ratanti-mouse CD4 monoclonal antibody, rat anti-mouse CD8 monoclonalantibody, rat anti-mouse F4/80 monoclonal antibody or normal rat IgG inantibody diluent. The samples are washed with PBS and incubated withbiotin-conjugated rabbit anti-rat IgG pretreated with 5% normal mouseserum. After washing with PBS, the samples are incubated withstreptavidin-horseradish peroxidase. After washing PBS, diaminobenzidineis used for visualization

Example 27 Models for Sjögren Syndrome

A compound's efficacy in treating Sjögren's syndrome can be tested usinganimal models known in the art, for example, those described in Chioriniet al., Journal of Autoimmunity 33: 190-196 (2009). Examples include:mouse model spontaneously developed in first filial generation of NZBmice crossed to NZW mice (see, e.g., Jonsson et al., Clin ImmunolImmunopathol 42: 93-101 (1987); mouse model induced by i.p. injection ofincomplete Freund's adjuvant (id.; Deshmukh et al., J Oral Pathol Med38: 42-27 (2009)); NOD mouse models wherein Sjögren's phenotype isdeveloped by specific genotypes (see, e.g., Cha et al., Arthritis Rheum46: 1390-1398 (2002); Kong et al., Clin Exp Rheumatol 16: 675-681(1998); Podolin et al., J Exp Med 178: 793-803 (1993); and Rasooly etal., Clin Immunol Immunopathol 81: 287-292 (1996)); mouse modeldeveloped in spontaneous lpr mutation; mouse model developed in Id3knock-out mice (see, e.g., Li et al., Immunity 21: 551-560 (2004));mouse model developed in PI3K knock-out mice (see, e.g., Oak et al.,Proc Natl Acad Sci USA 103: 16882-16887 (2006)); mouse model developedin BAFF over-expressing transgenic mice (see, e.g., Groom et al., J ClinInvest 109: 59-68 (2002)); mouse model induced by injection of Roantigen into BALB/c mice (see, e.g., Oh-Hora et al., Nat. Immunol 9:432-443 (2008)); mouse model induced by injection of carbonic anhydraseII (see, e.g., Nishimori et al., J Immunol 154: 4865-4873 (1995); mousemodel developed in IL-14 over-expressing transgenic mice (see, e.g.,Shen et al., J Immunol 177: 5676-5686 (2006)); and mouse model developedin IL-12 expressing transgenic mice (see, e.g., McGrath-Morrow et al.,Am J Physiol Lung Cell Mol Physiol 291: L837-846 (2006)).

Example 28 Models for Immune Complex Mediated Disease

The Arthus reaction is a type 3 immune response to immune complexes, andthus, can be a mechanistic model supporting therapeutic hypothesis forimmune complex mediated diseases such as rheumatoid arthritis, lupus andother autoimmune diseases. For example, PI3Kγ and δ deficient mice canbe used as experimental models of the Arthus reaction and provideassessment of therapeutic potential of a compound as to the treatment ofimmune complex mediated diseases. The Arthus reaction can be inducedusing the following exemplary procedures as described in Konrad et al.,Journal of Biological Chemistry (2008 283(48): 33296-33303.

PI3Kγ- and PI3Kδ-deficient mice are maintained under dry barrierconditions. Mice are anesthetized with ketamine and xylazine, and thetrachea is cannulated. Appropriate amount of protein G-purified anti-OVAIgG Ab is applied, and appropriate amount of OVA antigen is givenintravenously. For PI3K blocking experiments, wortmanin is givenintratracheally together with the application of anti-OVA igG. Mice arekilled at 2-4 hours after initiation of inflammation, and desired followup assessments can be performed using methods known in the art.

Example 29 PI3-Kinase Promega™ Assay

Promega ADP-Glo Max assay kit (Cat. No. V7002) can be utilized todetermine IC₅₀ values for α, β, δ and γ isoforms of human Class I PI3kinases (Millipore). Samples of kinase (20 nM a or 6, 40 nM β or γisoform) are incubated with compound for 15 minutes at room temperaturein reaction buffer (15 mM HEPES pH 7.4, 20 mM NaCl, 1 mM EGTA, 0.02%Tween 20, 10 mM MgCl₂, 0.2 mg/mL bovine-γ-globulins) followed byaddition of ATP/diC8-PtdInsP mixture to give final concentrations of 3mM ATP and 500 uM diC₈-PtdInsP. Reactions are incubated at roomtemperature for 2 hours followed by addition of 25 uL of stop solution.After a 40-minute incubation at room temperature, 50 uL of Promegadetection mix is added followed by incubation for 1 hour at roomtemperature. Plates are then read on Envision plate reader inlunimescence mode. Data are converted to % inhibition using thefollowing equation below:

${\% \mspace{14mu} {inhibition}} = {100 - \left( {\left\lbrack \frac{S - {Pos}}{{Neg} - {Pos}} \right\rbrack*100} \right)}$

where S is the sample luminescence, Pos is a positive control withoutadded PI3K, Neg is the negative control without added compound. Data arethen plotted as % inhibition vs compound concentration. Data fit to 4parameter logistic equation to determine IC₅₀ values:

${\% \mspace{14mu} {Inhibition}} = \frac{\max - \min}{1 - \left( \frac{{IC}_{50}^{h}}{\lbrack I\rbrack^{h\;}} \right)}$

Example 30 Isoform-Selective Cellular Assays

(a) PI3K-δ Selective Assay

A compound's ability in selectively inhibiting PI3K-δ can be assessedusing RAJI cells, i.e., B lymphocyte cells derived from lymphomapatients. Briefly, serum-starved RAJI cells are stimulated withanti-human IgM, thereby causing signaling through the B-cell receptors,as described in, for example, He et al., Leukemia Research (2009) 33:798-802. B-cell receptor signaling is important for the activation,differentiation, and survival of B cells and certain B-cell derivedcancers. Reduction of phospho-AKT is indicative of compounds that mayinhibit B-cell proliferation and function in certain diseases. Bymonitoring the reduction of phospho-AKT in stimulated RAJI cells (usingfor example, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kδ can be assessed.

(b) PI3K-γ Selective Assay

A compound's ability in selectively inhibiting PI3K-γ can be assessedusing RAW264.7 macrophages. Briefly, serum-starved RAW264.7 cells arestimulated with a known GPCR agonist C5a. See, e.g., Camps et al.,Nature Medicine (2005) 11(9):936-943. Cells can be treated with testcompounds prior to, simultaneously with, or subsequent to thestimulation by C5a. RAW 264.7 cells respond to the complement componentfragment C5a through activation of the C5a receptor, and the C5areceptor activates macrophages and induces cell migration. Testcompounds' ability to inhibit C5a-mediated AKT phosphorylation isindicative of selective inhibition of PI3K-γ. Thus, by monitoring thereduction of phospho-AKT in stimulated RAW 264.7 cells (using forexample, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kγ can be assessed.

Certain compounds provided herein were tested in RAW 264.7 cell modelusing procedures as described above. The IC₅₀ values for phospho-AKT aresummarized in Table 2.

(c) PI3K-α Selective Assay

A compound's ability in selectively inhibiting PI3K-α can be assessedusing SKOV-3 cells, i.e., human ovarian carcinoma cell line. Briefly,SKOV-3 cells, in which mutant PI3Kα is constitutively active, can betreated with test compounds. Test compounds' ability to inhibit AKTphosphorylation in SKOV-3 cells, therefore, is indicative of selectiveinhibition of PI3Kα. Thus, by monitoring the reduction of phospho-AKT inSKOV-3 cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kα can be assessed.

(d) PI3K-β Selective Assay

A compound's ability in selectively inhibiting PI3K-β can be assessedusing 786-O cells, i.e., human kidney carcinoma cell line. Briefly,786-O cells, in which PI3Kβ is constitutively active, can be treatedwith test compounds. Test compounds' ability to inhibit AKTphosphorylation in 786-O cells, therefore, is indicative of selectiveinhibition of PI3Kβ. Thus, by monitoring the reduction of phospho-AKT in786-O cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kβ can be assessed.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described will become apparent to thoseskilled in the art from the foregoing description. Such modificationsare intended to fall within the scope of the appended claims Variouspublications, patents and patent applications are cited herein, thedisclosures of which are incorporated by reference in their entireties.

What is claimed is:
 1. A compound of Formula I″:

or a pharmaceutically acceptable form thereof, wherein R is halo, C₁-C₈alkyl optionally substituted with one or more halo, or

is a (5-14 membered fused bicyclic saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of N, O, and S) or (5-14 membered fused bicyclic saturated,unsaturated, or aromatic carbocycle); wherein the heterocycle orcarbocycle is optionally substituted with one or more substituentsselected from R^(2a), R^(3a), R^(4a), R^(6a), (R^(5a))_(n), and R^(1d);n is 1, 2, or 3; L is a bond or —NR^(1e); W_(d) is selected from

X₁ is N or CR^(1f); X₂ is N or CR^(2f); X₃ is N or CR^(3f); X₄ is N orCR^(4f); X₅ is N or CR^(5f); R^(1a) is selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, OH,OR¹⁰, NH₂, NHR¹⁰; NR¹⁰R¹⁰, NR¹⁰COR¹⁰, COH, C(O)R¹⁰, COOH, COOR¹⁰, CONH₂,CONHR¹⁰, CONR¹⁰R¹⁰, CN, halo, NO₂, haloalkyl, (3-14 membered saturated,unsaturated, or aromatic carbocycle), and (3-14 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of N, O, and S); wherein each ofalkyl, alkenyl, alkynyl, haloalkyl, carbocycle, or heterocycle isoptionally substituted with one or more R¹¹; each instance of R¹⁰ isindependently selected from the group consisting of hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈ alkyl), NH₂,NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl),NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 memberedsaturated, unsaturated, or aromatic carbocycle), and (3-14 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of N, O, and S); eachinstance of R¹¹ is independently selected from the group consisting ofhydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂,haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH,CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated, unsaturated, oraromatic carbocycle), and (3-14 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of N, O, and S); each instance of R^(2a), R^(3a),R^(4a), R^(5a), and R^(6a) is independently selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo,oxo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl),N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈alkyl)₂, COH, CO(C₁-C₈ COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl),N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated, unsaturated, oraromatic carbocycle), and (3-14 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of N, O, and S); R^(1b), R^(2b), R^(3b), R^(4b),and R^(5b) each is independently selected from the group consisting ofhydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂,haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH,CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated, unsaturated, oraromatic carbocycle), and (3-14 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of N, O, and S); R^(1c) is selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo,OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈alkyl)₂, haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 membered saturated,unsaturated, or aromatic carbocycle), and (3-14 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of N, O, and S); R^(2c) is selectedfrom the group consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl),CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl),NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), (3-14 memberedsaturated, unsaturated, or aromatic carbocycle), and (3-14 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of N, O, and S); andR^(1d) is selected from the group consisting of hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, and C₂-C₈ alkynyl; R^(1e) is selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl;R^(1f) is selected from the group consisting of NH₂, NH(C₁-C₈ alkyl),N(C₁-C₈ alkyl)₂, hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂, haloalkyl, CN, NO₂, CONH₂,CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH,COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl),(3-14 membered saturated, unsaturated, or aromatic carbocycle), and(3-14 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from the group consisting ofN, O, and S); R^(2f), R^(3f), R^(4f), and R^(5f) each is independentlyselected from the group consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈ alkyl), OCF₃, OCF₂H, OCFH₂,NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂, haloalkyl, CN, NO₂, CONH₂,CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH, CO(C₁-C₈ alkyl), COOH,COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl),(3-14 membered saturated, unsaturated, or aromatic carbocycle), and(3-14 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from the group consisting ofN, O, and S); provided that W_(d) is not

and provided that when W_(d) is

then R^(2f) is not hydrogen.
 2. The compound of claim 1, wherein R ishalogen.
 3. The compound of claim 2, wherein R is Cl.
 4. The compound ofclaim 1, wherein R is C₁-C₈ alkyl optionally substituted with one ormore halo.
 5. The compound of claim 1, wherein the compound is acompound of Formula I′:

or a pharmaceutically acceptable form thereof.
 6. The compound of anyone of claims 1-4, wherein W_(d) is


7. The compound of any one of claims 1-4, wherein W_(d) is


8. The compound of claim 5, wherein the compound of Formula I′ is acompound of Formula I:

or a pharmaceutically acceptable form thereof.
 9. The compound of anyone of claims 1-8, wherein R^(1f) is NH₂, NH(C₁-C₈ alkyl), or N(C₁-C₈alkyl)₂.
 10. The compound of claim 9, wherein R^(1f) is NH₂.
 11. Thecompound of any one of claims 1-10, wherein R^(2f), R^(3f), R⁴, andR^(5f) each is independently selected from the group consisting ofhydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo, OH, O(C₁-C₈alkyl), OCF₃, OCF₂H, OCFH₂, NH₂, NH(C₁-C₈ alkyl), N(C₁-C₈ alkyl)₂,haloalkyl, CN, NO₂, CONH₂, CONH(C₁-C₈ alkyl), CON(C₁-C₈ alkyl)₂, COH,CO(C₁-C₈ alkyl), COOH, COO(C₁-C₈ alkyl), NHCO(C₁-C₈ alkyl), and N(C₁-C₈alkyl)CO(C₁-C₈ alkyl).
 12. The compound of claim 11, wherein R^(2f),R^(3f), R^(4f), and R^(5f) each is independently hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 13. The compound of claim 12, whereinR^(2f), R^(3f), R^(4f), and R^(5f) are hydrogen.
 14. The compound of anyone of claims 1-13, wherein

is a (8-10 membered fused bicyclic saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of N, O, and S) or (8-10 membered fused bicyclic saturated,unsaturated, or aromatic carbocycle).
 15. The compound of claim 14,wherein A is 6-membered heterocycle or carbocycle and B is 6-memberedheterocycle or carbocycle.
 16. The compound of claim 15, wherein A is6-membered heterocycle and B is 6-membered carbocycle.
 17. The compoundof claim 15, wherein A is 6-membered heterocycle and B is 6-memberedheterocycle.
 18. The compound of claim 15, wherein


19. The compound of claim 18, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 20. The compound of claim15, wherein


21. The compound of claim 20, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 22. The compound of claim15, wherein


23. The compound of claim 22, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 24. The compound of claim15, wherein


25. The compound of claim 24, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 26. The compound of anyone of claims 18-25, wherein R^(2a), R^(3a), and R^(4a) each isindependently hydrogen, C₁-C₈ alkyl, or halo.
 27. The compound of claim26, wherein R^(2a), R^(3a), and R^(4a) are hydrogen.
 28. The compound ofclaim 26, wherein R^(2a) is halo, and R^(3a) and R^(4a) are hydrogen.29. The compound of claim 14, wherein A is 6-membered heterocycle orcarbocycle and B is 5-membered heterocycle or carbocycle.
 30. Thecompound of claim 29, wherein A is 6-membered heterocycle and B is5-membered heterocycle.
 31. The compound of claim 29, wherein A is6-membered heterocycle and B is 5-membered carbocycle.
 32. The compoundof claim 29, wherein


33. The compound of claim 32, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 34. The compound of claim29, wherein


35. The compound of claim 34, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 36. The compound of anyone of claims 32-35, wherein R^(2a) and R^(3a) each is independentlyhydrogen, C₁-C₈ alkyl, or halo.
 37. The compound of claim 36, whereinR^(2a) and R^(3a) are hydrogen.
 38. The compound of claim 36, whereinR^(2a) is halo, and R^(3a) is hydrogen.
 39. The compound of claim 14,wherein A is 5-membered heterocycle or carbocycle and B is 6-memberedheterocycle or carbocycle.
 40. The compound of claim 39, wherein A is5-membered heterocycle and B is 6-membered heterocycle.
 41. The compoundof claim 39, wherein A is 5-membered heterocycle and B is 6-memberedcarbocycle.
 42. The compound of claim 39, wherein


43. The compound of claim 42, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 44. The compound of 42 or43, wherein R^(1d) is hydrogen or C₁-C₈ alkyl.
 45. The compound of claim44, wherein R^(1d) is hydrogen.
 46. The compound of claim 44, whereinR^(1d) is methyl.
 47. The compound of any one of claims 42-46, whereineach instance of R^(5a) is independently hydrogen, C₁-C₈ alkyl, or halo.48. The compound of claim 47, wherein each instance of R^(5a) isindependently hydrogen.
 49. The compound of any one of claims 42-48,wherein n is
 1. 50. The compound of any one of claims 42-48, wherein nis
 2. 51. The compound of any one of claims 42-48, wherein n is
 3. 52.The compound of claim 14, wherein A is 5-membered heterocycle orcarbocycle and B is 5-membered heterocycle or carbocycle.
 53. Thecompound of claim 52, wherein A is 5-membered heterocycle and B is5-membered heterocycle.
 54. The compound of claim 52, wherein


55. The compound of claim 54, wherein the compound of Formula I′ is acompound of the formula:

or a pharmaceutically acceptable form thereof.
 56. The compound of anyone of claim 54 or 55, wherein each instance of R^(5a) is independentlyhydrogen, C₁-C₈ alkyl, or halo.
 57. The compound of claim 56, whereinR^(5a) is hydrogen.
 58. The compound of any of claims 1-57, whereinR^(1a) is hydrogen, C₁-C₈ alkyl, or 3-14 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of N, O, and S.
 59. The compound ofclaim 58, wherein R^(1a) is C₁-C₈ alkyl.
 60. The compound of claim 58,wherein R^(1a) is 3-14 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of N, O, and S.
 61. The compound of claim 60, wherein R^(1a)is 5- or 6-membered aromatic heterocycle containing one or more Nheteroatoms.
 62. The compound of claim 61, wherein the heterocycle isoptionally substituted with one or more C₁-C₈ alkyl.
 63. The compound ofany of claims 1-62, wherein R^(1b), R^(2b), R^(3b), R^(4b), and R^(5b)are hydrogen.
 64. The compound of any of claims 1-63, wherein R^(1c) isC₁-C₈ alkyl.
 65. The compound of claim 64, wherein R^(1c) is methyl. 66.The compound of any of claims 1-65, wherein R^(2c) is hydrogen or C₁-C₈alkyl.
 67. The compound of claim 66, wherein R^(2c) is hydrogen.
 68. Thecompound of claim 1, wherein the compound is a compound selected fromTable 1, Table 2, Table 3, and Table 4, or a pharmaceutically acceptableform thereof.
 69. A pharmaceutical composition comprising a compound ofany one of claims 1-68 and a pharmaceutically acceptable excipient. 70.The pharmaceutical composition of claim 69, further comprises one ormore therapeutic agent.
 71. A method of treating or preventing a PI3Kmediated disorder in a subject comprising administering an effectiveamount of a compound of any one of claims 1-68 or a pharmaceuticalcomposition of claim 69 or 70 to the subject.
 72. A kit comprising acompound of any one of claims 1-68 or a pharmaceutical composition ofclaim 69 or 70.